Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals

ABSTRACT

The present invention relates to compounds of the formula I, 
                         
wherein A, Y, Z, R 20  to R 22  and R 50  have the meanings indicated in the claims, which are pharmaceutically active compounds. Specifically, they are inhibitors of the endothelial differentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPA 1  receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

The present invention relates to compounds of the formula I,

wherein A, Y, Z, R²⁰ to R²² and R⁵⁰ have the meanings indicated below,which are valuable pharmaceutical active compounds. Specifically, theyare inhibitors of the endothelial differentiation gene receptor 2(Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and isalso termed as LPA₁ receptor, and are useful for the treatment ofdiseases such as atherosclerosis, myocardial infarction and heartfailure, for example. The invention furthermore relates to processes forthe preparation of the compounds of the formula I, their use andpharmaceutical compositions comprising them.

LPA is a group of endogenous lysophospholipid derivatives including1-oleoyl-sn-glycerol 3-phosphate, for example. LPA activatesG-protein-coupled receptors (GPCR's) from the endothelialdifferentiation gene receptor family which belong to thelysophospholipid receptors. LPA signaling exerts a variety ofpleiotropic biological responses on many different cell types whichinterfere with processes such as cell proliferation, cell growth, cellhypertrophy, re-differentiation, cell retraction, cell contraction, cellmigration, cell survival or inflammation. The Edg receptor family,originally identified as a family of orphan GPCR's, currently compriseseight different members which were recently termed according to theirrespective ligand as LPA receptors or S1P receptors(sphingosine-1-phosphate receptors). According to the nomenclature ofthe International Union of Basic and Clinical Pharmacology (IUPHAR), LPAreceptors Edg-2, Edg-4 and Edg-7 are now also termed as LPA₁, LPA₂ andLPA₃ receptor (cf. I. Ishii et al., Annu. Rev. Biochem. 73 (2004),321-354).

LPA is generated mainly in the extracellular compartment by differentpathways predominantly by the cancer cell motility factor autotaxinwhich was recently found to be identical with lysophospholipase D. LPAcan also be generated by alternative routes involving phospholipasehydrolysis (PLA₁ and PLA₂) or other mechanisms such as de novophospholipid synthesis. Although LPA, in contrast to otherphospholipids, is highly soluble in water, in plasma it is carried bydifferent binding proteins such as albumin and gelsolin which display ahigh affinity to LPA and from which it can be released. Underpathophysiological conditions, levels of LPA can be elevated to anundesirable amount and thus increase LPA-mediated signaling and lead todetrimental processes such as abnormal cell proliferation, for example.Blocking LPA signaling, for example by Edg-2 inhibitors, allows toprevent such processes.

For example, increased liberation of LPA was observed during plateletactivation and blood clotting and at sites of inflammation (T. Sano et.al., J. Biol. Chem. 277 (2002), 21197-21206). After acute myocardialinfarction (AMI) in humans, LPA serum levels were significantly raisedin humans to about 6-fold higher concentrations, and LPA was regarded tobe involved in the pathophysiological processes in the cardiovascularsystem related to AMI (X. Chen et al., Scand. J. Clin. Lab. Invest. 63(2003), 497-503). The importance of LPA and its receptor Edg-2 for thepathophysiological processes after myocardial infarction such as cardiacremodeling and for the prevention of cardiac hypertrophy and heartfailure was confirmed in further investigations (J. Chen et al., J.Cell. Biochem. 103 (2008), 1718-1731). LPA was shown to be generatedduring mild oxidation of low density lipoprotein (LDL) particles and tobe accumulated in the lipid core of human atherosclerotic plaques (W.Siess et al., Proc. Natl. Acad. Sci. 96 (1999), 6931-6936). Furthermore,LPA was identified as an important bioactive component of moxLDL (mildlyoxidized low density lipoprotein) leading to platelet activation, and itwas shown that the effects of LPA, moxLDL or lipid core extracts fromhuman atherosclerotic plaques on platelet activation could be abrogatedby the Edg-2/Edg-7 receptor inhibitor dioctanoylglycerol pyrophosphateDGPP(8:0), implicating a causative role of LPA-mediated Edg receptorsignaling in platelet aggregation and usefulness of such LPA receptorinhibitors in the treatment of cardiovascular diseases (E. Rother etal., Circulation 108 (2003), 741-747).

Further findings underline the detrimental role of LPA during initiationand progression of cardiovascular diseases such as atherosclerosis, leftventricular remodeling and heart failure. LPA leads to pertussistoxin-sensitive, NFκB (nuclear factor kappa B)-mediated pro-inflammatoryresponses of endothelial cells including upregulation of chemokines likemonocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL8) (A.Palmetshofer et al., Thromb. Haemost. 82 (1999), 1532-1537) and exposureof endothelial cell adhesion molecules like E-selectin or intercellularadhesion molecule-1 (ICAM-1) (H. Lee et al., Am. J. Physiol. 287 (2004),C1657-C1666). Direct evidence for the involvement of Edg-2 receptorsarises from recent studies which demonstrate that LPA induces oxidativestress in vascular smooth muscle cells and endothelial cells which wasattenuated by pharmacological inhibition by DGPP(8:0) or THG1603, aspecific Edg-2 receptor antagonist (U. Kaneyuki et al., VascularPharmacology 46 (2007), 286-292; S. Brault et al., Am. J. Physiol.Regul. Integr. Comp. Physiol. 292 (2007), R1174-R1183). In vascularsmooth muscle cells, LPA leads to pertussis toxin-sensitive Ca²⁺ releasefrom internal stores, to activation of 42 kDa mitogen-activated proteinkinase (p42MAPK) and to cell proliferation (S. Seewald et al.,Atherosclerosis 130 (1997), 121-131). Intravascular injection of LPA wasshown to induce neointima formation in vivo (K. Yoshida et al.,Circulation 108 (2003), 1746-1752). On isolated adult cardiac myocytes,LPA leads to cellular hypertrophy and to activation of different kinasesknown to be relevant for a hypertrophic response (Y.-J. Xu et al.,Biochemical Pharmacology 59 (2000), 1163-1171). Studies on neonatalmyocytes confirmed a role of LPA in the induction of hypertrophy andrevealed the relevance of a rho kinase-dependent pathway (R.Hilal-Dandan et al., J. Mol. Cell. Cardiol. 36 (2004), 481-493). Therelevance of rho kinase underlines the involvement of the Edg-2receptors which, in contrast to Edg-7 receptors, are coupled toG_(α12/13) proteins. LPA furthermore attenuates the force of contractionin human myocardial ventricular and atrial preparations and impairsisoprenaline-induced fractional shortening of isolated adult ratventricular myocytes. The latter effects were reverted afterpre-incubation with pertussis toxin indicating the relevance of aGPCR-mediated and G_(αi/0)-mediated pathway (B. Cremers et al., J. Mol.Cell. Cardiol. 35 (2003), 71-80). LPA was also found to lead to enhancedmatrix generation and proliferation of cardiac fibroblasts (J. Chen etal., FEBS Letters 580 (2006), 4737-4745).

The importance of influencing Edg-2 receptor signaling and LPA-mediatedeffects for many diseases was confirmed by pharmacological approachesusing specific tool compounds or Edg-2 receptor knock-out mice or byexperimental silencing of the Edg-2 receptors. For example, therelevance of LPA-activated Edg receptors for renal diseases wasdemonstrated by different kinds of Edg-2/Edg-7 receptor inhibitors. Inone approach, it was shown that the LPA-induced proliferative responseof mesangial cells could be inhibited by the compound DGPP(8:0) (Y. Xinget al., Am. J. Physiol. Cell Physiol. 287 (2004), F1250-F1257). Inanother approach using the Edg-2/Edg-7 receptor inhibitor VPC12249 itwas demonstrated in an in vivo model of mouse renal ischemia reperfusionthat LPA displays a dual role in renoprotection. While Edg-4 receptorsignaling was shown to be beneficial, Edg-2 and Edg-7 receptor signalingaggravated renal injury, most probably due to enhanced infiltration ofleukocytes into the renal tissue, and should therefore be blocked fortreating or preventing ischemia/reperfusion-induced acute renal failure(M. D. Okusa et al., Am. J. Physiol. Renal Physiol. 285 (2003),F565-F574). The crucial role of Edg-2 receptors in the development oftubulointerstitial fibrosis was confirmed in a model of unilateralureteral obstruction (J. P. Pradere et al., J. Am. Soc. Nephrol. 18(2007), 3110-3118). In this model, renal injury was attenuated in Edg-2receptor knock-out mice or by pharmacological treatment with theEdg-2/Edg-7 receptor inhibitor Ki16425. The impact of the LPA/Edg-2receptor system in pulmonary fibrosis and vascular leakage was recentlyconfirmed by the finding that the bioactive content of LPA was increasedin bronchoalveolar fluid of humans suffering from idiopathic pulmonaryfibrosis. Edg-2 receptor knock-out mice were protected frombleomycin-induced lung injury and vascular leakage, as compared towild-type littermates (A. M. Tager et al., Nat. Med. 14 (2008), 45-54).

Direct involvement of Edg-2 receptors was recently demonstrated for theprogression of bone metastasis in vivo. Progression was reduced underpharmacological treatment with the Edg-2/Edg-7 receptor inhibitorKi16425 as well as after specific silencing of the Edg-2 receptors inthe same order of magnitude (A. Boucharaba et al., Proc. Natl. Acad.Sci. 103 (2006), 9643-9648). The relevance of Edg-2 receptors was alsoshown in vitro with respect to prostate cancer cell proliferation andmetastatic potential of human colon carcinoma cells (R. Guo et al.,Endocrinology 147 (2006), 4883-4892; D. Shida et al., Cancer Res. 63(2003), 1706-1711).

The relevance of LPA-mediated Edg-2 receptor signaling was alsodemonstrated in an in vivo model of neuropathic pain. Intrathecalinjection of LPA mimicked behavioral, morphological and biochemicalalterations similar to those observed after peripheral nerve injury.Non-redundant function of Edg-2 receptors was demonstrated in Edg-2receptor deficient mice which did not develop signs of neuropathic painafter nerve injury. Therefore, Edg-2 receptor signaling is regarded ascrucial in the initiation of neuropathic pain (M. Inoue et al., Nat.Med. 10 (2004), 712-718). Thus, it is evident that inhibition of theEdg-2 receptor and the effects of LPA by suitable inhibitors is anattractive approach for treating various diseases.

Certain compounds which exhibit Edg-2 inhibitory activity, have alreadybeen described. For example, as compounds which are structurally relatedto LPA, the above-mentioned compounds DGPP(8:0) or VPC12249 may bementioned. In WO 02/29001 and WO 2005/115150 amino compounds comprisinga phosphate group, phosphonate group or hydroxy group are describedwhich have activity as agonists or antagonists of LPA receptors. LPAreceptor antagonistic azole compounds which are characterized by acarbamate group in the 4-position of the azole ring, are described in EP1258484. The use of azole compounds, further heterocycles and othercompounds for modulating the Edg-2, Edg-3, Edg-4 and Edg-7 receptor isdescribed in WO 03/062392. Compounds which have LPA receptor, especiallyEdg-2, antagonistic activity and which comprise a β-alanine moietycarrying a biphenyl-2-carbonyl group on the amino group, or an alcoholgroup and at least three cyclic groups, are described in EP 1533294 andEP 1695955, respectively. But there still is a need for further Edg-2inhibitors which exhibit a favorable property profile and can be used inthe treatment of diseases such as the above-mentioned ones and otherdiseases in which LPA signaling and Edg-2 receptors play a role. Thepresent invention satisfies this need by providing theacylamino-substituted cyclic carboxylic acid derivatives of the formulaI defined below.

Certain acylamino-substituted cyclic carboxylic acid derivatives havealready been described. In WO 2004/011457, which relates to1-phenylpiperidin-3-one derivatives carrying a1-acylaminocyclohexylcarbonylamino substituent in the 4-position of thepiperidine ring and exhibiting cysteine protease inhibitory activity,the compounds 1-[(biphenyl-4-carbonyl)-amino]-cyclohexanecarboxylicacid, 1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylicacid,1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid, 1-[4-(2-piperidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid and1-{[4-(2-oxo-pyrrolidin-1-yl)-furan-2-carbonyl]-amino}-cyclohexanecarboxylicacid, i.e. the compounds of the formula I in which the ring A is anunsubstituted cyclohexane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and thering comprising Y and Z and carrying R²¹ and R²² is biphenyl-4-yl,4-(2-oxo-pyrrolidin-1-yl)-phenyl, 4-(2-pyrrolidin-1-yl-ethoxy)-phenyl,4-(2-piperidin-1-yl-ethoxy)-phenyl and4-(2-oxo-pyrrolidin-1-yl)-furan-2-yl, are disclosed as intermediates inthe synthesis of the pharmacological active compounds. In WO2004/052921, which relates to acylamino-substituted carboxamidescarrying a cyano group in the substituent on the carboxamide nitrogenatom and exhibiting likewise cysteine protease inhibitory activity, thecompoundI-(2′,3-dichloro-biphen-4-ylcarbonylamino)-cycloheptanecarboxylic acid(=1-[(2′,3-dichloro-biphenyl-4-carbonyl)-amino]-cycloheptanecarboxylicacid), i.e. the compound of the formula I in which the ring A is anunsubstituted cycloheptane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and thering comprising Y and Z and carrying R²¹ and R²² is2′,3-dichloro-biphen-4-yl (=2′,3-dichloro-biphenyl-4-yl), is disclosedas an intermediate in the synthesis of the pharmacological activecompounds. Elsewhere the said compound disclosed in WO 2004/052921 isidentified as1-[[(2,2′-dichloro[1,1]biphenyl)-4-yl)carbonyl)-amino]cycloheptanecarboxylicacid(=1-[(2,2′-dichloro-biphenyl-4-carbonyl)-amino]-cycloheptanecarboxylicacid), i.e. as the compound of the formula I in which the ring A is anunsubstituted cycloheptane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and thering comprising Y and Z and carrying R²¹ and R²² is2,2′-dichloro-biphenyl-4-yl. In U.S. Pat. No. 4,871,387, which relatesto pyri(mi)dyl-oxy- and -thio-benzoic acid derivatives exhibitingherbicidal and plant growth regulatory activity, the compoundI-[4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-benzoylamino]-cyclopentanecarboxylicacid ethyl ester, i.e. the compound of the formula I in which the ring Ais an unsubstituted cyclopentane ring, R²⁰ is hydrogen, R⁵⁰ is ethoxyand the ring comprising Y and Z and carrying R²¹ and R²² is4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl, is disclosed. In WO02/06232, which relates to azacycloalkanes carrying a phenyl group onthe ring nitrogen atom and a hydroxyalkyl-amino substituent on a ringcarbon atom and exhibiting agonistic activity on O₃ adrenergicreceptors, the compound1-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-cyclopropanecarboxylic acidmethyl ester, i.e. the compound of the formula I in which the ring A isan unsubstituted cyclopropane ring, R²⁰ is hydrogen, R⁵⁰ is methoxy andthe ring comprising Y and Z and carrying R²¹ and R²² is4-(4-oxo-piperidin-1-yl)-phenyl, is disclosed as an intermediate in thesynthesis of the pharmacological active compounds. In WO 99/49856, whichrelates to very broadly defined compounds which mediate immune orinflammatory response through the CD11/CD18 family of cellular adhesionmolecules, the compoundI-[2-chloro-4-(3-hydroxy-benzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylicacid, i.e. the compound of the formula I in which the ring A is anunsubstituted cyclopropane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and thering comprising Y and Z and carrying R²¹ and R²² is2-chloro-4-(3-hydroxy-benzylcarbamoyl)-phenyl, is disclosed.

A subject of the present invention is a compound of the formula I, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof,

-   wherein-   ring A is a 3-membered to 12-membered monocyclic, bicyclic or    spirocyclic ring which comprises 0, 1 or 2 identical or different    hetero ring members chosen from the series consisting of N, N(R⁰),    O, S, S(O) and S(O)₂, and which is saturated or comprises 1 double    bond, provided that ring A is not a bicyclo[3.1.0]hexane or    bicyclo[3.2.0]heptane ring carrying the groups N(R²⁰) and C(O)—R⁵⁰    in its position 3, and not an octahydropentalene, octahydroindene or    decahydroazulene ring carrying the groups N(R²⁰) and C(O)—R⁵⁰ in its    position 2, wherein ring A is optionally substituted on ring carbon    atoms by one or more identical or different substituents chosen from    the series consisting of halogen, R¹, R², (C₂-C₆)-alkenyl, HO—,    R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—,    R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R¹)—,    R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—,    H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—,    R¹—N(R¹)—S(O)₂—, F₅S—, NC—, oxo and methylene;-   Y is chosen from the series consisting of N(R¹⁰), S, O,    C(R¹²)═C(R¹³), N═C(R¹⁴) and C(R¹⁵)═N;-   Z is chosen from the series consisting of N and C(R¹⁶);-   R⁰ is chosen from the series consisting of hydrogen and R¹;-   R¹ is chosen from the series consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R² is (C₁-C₄)-alkyl which is substituted by one or more identical or    different substituents chosen from the series consisting of HO— and    (C₁-C₄)-alkyl-O—;-   R¹⁰ is chosen from the series consisting of hydrogen and R¹¹;-   R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ and R⁵⁸ are independently    of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸,    chosen from the series consisting of (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- which are all optionally    substituted by one or more identical or different substituents R⁷⁰;-   R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently of each other chosen    from the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,    HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—,    (C₁-C₄)-alkyl-C(O)— and NC—, or R¹³ or R¹⁴, together with the one of    the groups R²¹ and R²² which is not the group of the formula II,    forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2    chain members are identical or different hetero chain members chosen    from the series consisting of N(R¹⁷), O and S, but two hetero chain    members cannot be present in adjacent positions, and the other chain    members are identical or different groups C(R¹⁸)(R¹⁸);-   R¹⁷ and R²⁵ are independently of each other chosen from the series    consisting of hydrogen and (C₁-C₄)-alkyl;-   R¹⁸, independently of each other group R¹⁸, is chosen from the    series consisting of hydrogen, fluorine and (C₁-C₄)-alkyl, or two of    the groups R¹⁸ bonded to the same carbon atom, together with the    carbon atom carrying them, form a 3-membered to 6-membered    cycloalkane ring which is optionally substituted by one more    identical or different substituents chosen from the series    consisting of fluorine and (C₁-C₄)-alkyl;-   R²⁰ is chosen from the series consisting of hydrogen and    (C₁-C₄)-alkyl;-   one of the groups R²¹ and R²² is a group of the formula II    R²⁴—R²³—  II-   and the other of the groups R²¹ and R²² is chosen from the series    consisting of hydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—,    R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—,    R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—,    R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—,    R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—,    O₂N— and Het¹, or together with R¹³ or R¹⁴ forms a chain as    specified in the definition of R¹³ and R¹⁴;-   R²³ is a direct bond or a chain consisting of 1 to 5 chain members    of which 0, 1 or 2 chain members are identical or different hetero    chain members chosen from the series consisting of N(R²⁵), O, S,    S(O) and S(O)₂, but two hetero chain members can be present in    adjacent positions only if one of them is chosen from the series    consisting of S(O) and S(O)₂ and the other is chosen from the series    consisting of N(R²⁵), O and S, and the other chain members are    identical or different groups C(R²⁶)(R²⁶);-   R²⁴ is a 3-membered to 10-membered, monocyclic or bicyclic ring,    which is saturated and contains 0 or 1 hetero ring members, or is    unsaturated and contains 0, 1 or 2 identical or different hetero    ring members, wherein the hetero ring members are chosen from the    series consisting of N, N(R³²), O, S, S(O) and S(O)₂, and wherein    the ring is optionally substituted on ring carbon atoms by one or    more identical or different substituents chosen from the series    consisting of halogen, R³³, oxetanyl, HO—, R³³—O—, R³³—C(O)—O—,    R³³—S(O)₂—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,    R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,    H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,    H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—,    R³³—C(O)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—,    R³³—N(R³³)—C(O)—, H₂N—S(O)₂—, R³³—NH—S(O)₂—, R³³—N(R³³)—S(O)₂—, NC—,    O₂N— and oxo;-   R²⁶, independently of each other group R²⁶, is chosen from the    series consisting of hydrogen, fluorine, (C₁-C₄)-alkyl and HO—, or    two groups R²⁶ bonded to the same carbon atom together are oxo, or    two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together    with the comprised chain members, form a 3-membered to 7-membered    monocyclic ring which is saturated and contains 0, 1 or 2 identical    or different hetero ring members chosen from the series consisting    of N, N(R³⁴), O, S, S(O) and S(O)₂, which ring is optionally    substituted on ring carbon atoms by one more identical or different    substituents chosen from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R³² and R³⁴ are independently of each other chosen from the series    consisting of hydrogen, R³⁵, R³⁵—S(O)₂—, R³⁵—C(O)—, R³⁵—O—C(O)— and    phenyl;-   R⁵⁰ is chosen from the series consisting of R⁵¹—O— and R⁵²—N(R⁵³)—;-   R⁵¹ is chosen from the series consisting of hydrogen and R⁵⁴;-   R⁵² is chosen from the series consisting of hydrogen, R⁵⁵, NC— and    R⁵⁶—S(O)₂—;-   R⁵³ is chosen from the series consisting of hydrogen and R⁵⁷;-   R⁵⁶ is chosen from the series consisting of R⁵⁸ and phenyl;-   R⁶⁰, independently of each other group R⁶⁰, is chosen from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R⁷⁰ is chosen from the series consisting of HO—, R⁷⁰—O—,    R⁷¹—O(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—,    R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—, R⁷¹—S(O)₂—N(R⁷¹)—,    HO—C(O)—, R⁷¹—O—O(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—, R⁷¹—N(R⁷¹)—C(O)—,    H₂N—S(O)₂—, R⁷¹—NH—S(O)₂—, R⁷¹—N(R⁷¹)—S(O)₂— and oxo;-   R⁷¹, independently of each other group R⁷¹, is chosen from    (C₁-C₄)-alkyl, (C₃-C₄)-cycloalkyl and    (C₃-C₄)-cycloalkyl-(C₁-C₂)-alkyl-;-   Het¹ is a monocyclic 4-membered to 7-membered heterocyclic ring    which comprises 1 or 2 identical or different hetero ring members    chosen from the series consisting of N, N(R⁶⁰), O, S, S(O) and    S(O)₂, which ring is saturated and is optionally substituted by one    or more identical or different substituents chosen from the series    consisting of fluorine and (C₁-C₄)-alkyl;-   m, independently of each other number m, is an integer chosen from    the series consisting of 0, 1 and 2;-   phenyl, independently of each other group phenyl, is optionally    substituted by one or more identical or different substituents    chosen from the series consisting of halogen, (C₁-C₄)-alkyl,    (C₁-C₄)-alkyl-O— and NC—, unless specified otherwise;-   cycloalkyl, independently of each other group cycloalkyl, and    independently of any other substituents on cycloalkyl, is optionally    substituted by one or more identical or different substituents    chosen from fluorine and (C₁-C₄)-alkyl;-   alkyl, alkenyl and alkynyl, independently of each other group alkyl,    alkenyl and alkynyl, and independently of any other substituents on    alkyl, alkenyl and alkynyl, is optionally substituted by one or more    fluorine substituents;-   provided that the compound of the formula I is not    1-[(biphenyl-4-carbonyl)-amino]-cyclohexanecarboxylic acid,    1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic    acid,    1-[4-(2-piperidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic    acid,    1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylic    acid,    1-{[4-(2-oxo-pyrrolidin-1-yl)-furan-2-carbonyl]-amino}-cyclohexanecarboxylic    acid,    1-[(2′,3-dichloro-biphenyl-4-carbonyl)-amino]-cycloheptanecarboxylic    acid,    1-[4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-benzoylamino]-cyclopentanecarboxylic    acid ethyl ester,    1-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-cyclopropanecarboxylic    acid methyl ester or    1-[2-chloro-4-(3-hydroxy-benzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylic    acid.

If structural elements such as groups, substituents or numbers, forexample, can occur several times in the compounds of the formula I, theyare all independent of each other and can in each case have any of theindicated meanings, and they can in each case be identical to ordifferent from any other such element. In a dialkylamino group, forexample, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear(straight-chain) or branched. This also applies if these groups aresubstituted or are part of another group, for example an alkyl-O— group(alkyloxy group, alkoxy group) or an HO-substituted alkyl group(hydroxyalkyl group). Depending on the respective definition, the numberof carbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6, or 1, 2, 3or 4, or 1, 2 or 3, or 1 or 2, or 1. In one embodiment of the invention,a (C₁-C₆)-alkyl group present in any position of the compounds of theformula I is a (C₁-C₄)-alkyl group, in another embodiment a(C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkyl group, inanother embodiment a (C₂-C₃)-alkyl group, in another embodiment a methylgroup, where any (C₁-C₆)-alkyl group present in the compounds of theformula I can independently of each other (C₁-C₆)-alkyl group be a groupof any of these embodiments. In one embodiment of the invention, a(C₁-C₄)-alkyl group present in any position of the compounds of theformula I is a (C₁-C₃)-alkyl group, in another embodiment a(C₁-C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, inanother embodiment a methyl group, where any (C₁-C₄)-alkyl group presentin the compounds of the formula I can independently of each other(C₁-C₄)-alkyl group be a group of any of these embodiments. Examples ofalkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butylincluding n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl includingn-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexylincluding n-hexyl, 3,3-dimethylbutyl and isohexyl. Examples of alkyl-O—groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy. Examples of alkyl-S(O)_(m)— are methylsulfanyl-(CH₃—S—), methanesulfinyl- (CH₃—S(O)—), methanesulfonyl (CH₃—S(O)₂—),ethylsulfanyl-(CH₃—CH₂—S—), ethanesulfinyl- (CH₃—CH₂—S(O)—),ethanesulfonyl (CH₃—CH₂—S(O)₂—), 1-methylethylsulfanyl- ((CH₃)₂CH—S—),1-methylethanesulfinyl- ((CH₃)₂CH—S(O)—), 1-methylethanesulfonyl((CH₃)₂CH—S(O)₂—). In one embodiment of the invention the number m ischosen from 0 and 2, wherein all numbers m are independent of each otherand can be identical or different. In another embodiment the number m inany of its occurrences is, independent of its meaning in otheroccurrences, 0. In another embodiment the number m in any of itsoccurrences is, independent of its meaning in other occurrences, 2.

A substituted alkyl group can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to thedefinitions of all groups in the compounds of the formula I. An alkylgroup which is optionally substituted by one or more fluorinesubstituents can be unsubstituted, i.e. not carry fluorine substituents,or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11fluorine substituents, or by 1, 2, 3, 4, 5, 6 or 7 fluorinesubstituents, or by 1, 2, 3, 4 or 5 fluorine substituents, or by 1, 2 or3 fluorine substituents, which can be located in any positions. Forexample, in a fluoro-substituted alkyl group one or more methyl groupscan carry three fluorine substituents each and be present astrifluoromethyl groups, and/or one or more methylene groups (CH₂) cancarry two fluorine substituents each and be present as difluoromethylenegroups. The explanations with respect to the substitution of a group byfluorine also apply if the group additionally carries other substituentsand/or is part of another group, for example of an alkyl-O— group.Examples of fluoro-substituted alkyl groups are trifluoromethyl,2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,4,4,4-trifluorobutyl and heptafluoroisopropyl. Examples offluoro-substituted alkyl-O— groups are trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.Examples of fluoro-substituted alkyl-S(O)_(m)— groups aretrifluoromethylsulfanyl- (CF₃—S—), trifluoromethanesulfinyl-(CF₃—S(O)—)and trifluoromethanesulfonyl (CF₃—S(O)₂—).

The above explanations with respect to alkyl groups applycorrespondingly to unsaturated hydrocarbon residues, i.e. alkenylgroups, which in one embodiment of the invention contain one doublebond, and alkynyl groups, which in one embodiment of the inventioncontain one triple bond. Thus, for example, alkenyl groups and alkynylgroups can likewise be linear or branched, and substituted alkenyl andalkynyl groups can be substituted in any positions, provided that theresulting compound is sufficiently stable and is suitable as apharmaceutical active compound. Double bonds and triple bonds can bepresent in any positions. The number of carbon atoms in an alkenyl oralkynyl group can be 2, 3, 4, 5 or 6, for example 2, 3, 4 or 5, or 2, 3or 4. Examples of alkenyl and alkynyl are ethenyl (vinyl), prop-1-enyl,prop-2-enyl (allyl), but-2-enyl, 2-methylprop-2-enyl,3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, 4-methylhex-4-enyl, ethynyl,prop-1-ynyl, prop-2-ynyl (propargyl), but-2-ynyl, but-3-ynyl,4-methylpent-2-ynyl, hex-4-ynyl and hex-5-ynyl. In one embodiment of theinvention, an alkenyl or alkynyl group contains at least three carbonatoms and is bonded to the remainder of the molecule via a carbon atomwhich is not part of a double bond or triple bond.

The above explanations with respect to alkyl groups applycorrespondingly to alkanediyl groups (divalent alkyl groups), includingchains of one or more groups C(R²⁶)(R²⁶) and chains of one or moregroups C(R¹⁸)(R¹⁸) which groups as such and chains of such groups arealkanediyl groups in case R²⁶ and R¹⁸ is chosen from hydrogen and(C₁-C₄)-alkyl, or are substituted alkanediyl groups in case any of thegroups R²⁶ and R¹⁸ has a meaning different from hydrogen and(C₁-C₄)-alkyl. Likewise, the alkyl part of a substituted alkyl group canalso be regarded as an alkanediyl group. Thus, alkanediyl groups canalso be linear or branched, the bonds to the adjacent groups can belocated in any positions and can start from the same carbon atom or fromdifferent carbon atoms, and they can be substituted by fluorinesubstituents. Examples of alkanediyl groups are —CH₂—, —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—.Examples of fluoro-substituted alkanediyl groups, which can contain 1,2, 3, 4, 5 or 6 fluorine substituents, or 1, 2, 3 or 4 fluorinesubstituents, or 1 or 2 fluorine substituents for example, are —CHF—,—CF₂—, —CF₂—CH₂—, —CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂—,—C(CH₃)₂—CF₂—, —CF₂—C(CH₃)₂—.

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3,4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups which areoptionally substituted by one or more (C₁-C₄)-alkyl substituents, can beunsubstituted, i.e. not carry alkyl substituents, or substituted, forexample by 1, 2, 3 or 4, or by 1 or 2, identical or different(C₁-C₄)-alkyl substituents, for example by methyl groups, whichsubstituents can be located in any positions. Examples of suchalkyl-substituted cycloalkyl groups are 1-methylcyclopropyl,2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl,1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl,4-tert-butylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl. Cycloalkylgroups which are optionally substituted by one or more fluorinesubstituents, can be unsubstituted, i.e. not carry fluorinesubstituents, or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9,10 or 11 fluorine substituents, or by 1, 2, 3, 4, 5 or 6 fluorinesubstituents, or by 1, 2, 3 or 4 fluorine substituents, or by 1 or 2fluorine substituents. The fluorine substituents can be located in anypositions of the cycloalkyl group and can also be located in an alkylsubstituent on the cycloalkyl group. Examples of fluoro-substitutedcycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl,3,3-difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl and3,3,4,4,5,5-hexafluorocyclohexyl. Cycloalkyl groups can also besubstituted simultaneously by fluorine and alkyl. Examples of the group(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- are cyclopropylmethyl-,cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-,cycloheptylmethyl-, 1-cyclopropylethyl-, 2-cyclopropylethyl-,1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-cyclopentylethyl-,2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-,1-cycloheptylethyl-, 2-cycloheptylethyl-. The explanations with respectcycloalkyl groups apply correspondingly to unsaturated cycloalkyl groupssuch as cycloalkenyl groups which can occur in the group R²⁴ and whichin one embodiment of the invention contain one double bond which can bepresent in any positions, and to divalent cycloalkyl groups(cycloalkanediyl groups), which latter groups can occur in case two ofthe groups R²⁶ together with the comprised chain members form a ring ortwo of the groups R¹⁸ together with the carbon atom carrying them form aring. Likewise, the cycloalkyl part of a substituted cycloalkyl groupcan also be regarded as a cycloalkanediyl group. Thus, for example, thebonds through which a cycloalkanediyl group, such as a ring formed bytwo of the groups R²⁶ together with the comprised chain members, isconnected to the adjacent groups, can be located in any positions andcan start from the same ring carbon atom or from different ring carbonatoms, unless specified otherwise.

In substituted phenyl groups, including phenyl groups which representthe 3-membered to 10-membered, monocyclic or bicyclic ring representingR²⁴, the substituents can be located in any positions. Inmonosubstituted phenyl groups, the substituent can be located in the2-position, the 3-position or the 4-position. In disubstituted phenylgroups, the substituents can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. Intrisubstituted phenyl groups, the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position or 3,4,5-position. If a phenyl group carries foursubstituents, some of which can be fluorine atoms, for example, thesubstituents can be located in 2,3,4,5-position, 2,3,4,6-position or2,3,5,6-position. If a polysubstituted phenyl group or any otherpolysubstituted group such as a heteroaryl group carries differentsubstituents, each substituent can be located in any suitable position,and the present invention comprises all positional isomers. The numberof substituents in a substituted phenyl group can be 1, 2, 3, 4 or 5. Inone embodiment of the invention, a substituted phenyl group, andlikewise another substituted group such as a heteroaryl group, carries1, 2 or 3, for example 1 or 2, identical or different substituents.

In heterocyclic groups, including the group Het¹ and heterocyclic ringswhich can be present in structural elements in the compounds of theformula I, such as the ring A, or the 3-membered to 10-membered ringrepresenting R²⁴, or a ring formed by a group R²⁵ and a group R²⁶together with the comprised chain members, or a ring formed by a groupR¹³ or R¹⁴ with one of the groups R²¹ and R²² and the carbon atomscarrying these groups, for example, the hetero ring members specified inthe respective definition can be present in any combination and locatedin any suitable ring positions, provided that the resulting group andthe compound of the formula I are sufficiently stable and suitable as apharmaceutical active compound. In one embodiment of the invention twooxygen atoms in any heterocyclic ring in the compounds of the formula Icannot be present in adjacent ring positions. In another embodiment ofthe invention two hetero ring members in any non-aromatic heterocyclicring in the compounds of the formula I cannot be present in adjacentring positions. In another embodiment two hetero ring members from theseries consisting of O, S and N atoms carrying a hydrogen atom or asubstituent, cannot be present in adjacent ring positions. Examples ofsuch series are the hetero ring members O, S and N(R⁰), or O, S andN(R³²), or O, S and N(R³⁴), or O, S and N(R⁶⁰), or the hetero chainmembers O, S and N(R¹⁷) which are part of a ring. In another embodimentof the invention two hetero ring members from the series consisting ofS(O) and S(O)₂ cannot be present in adjacent ring positions. In anaromatic heterocyclic ring the choice of hetero ring members and theirpositions is limited by the prerequisite that the ring is aromatic, i.e.it comprises a cyclic system of six delocalized pi electrons. Theresidue of a monocyclic, 5-membered or 6-membered, aromatic heterocyclicring, which can occur as the 3-membered to 10 membered ring representingR²⁴, can also be designated as monocyclic, 5-membered or 6-memberedheteroaryl group. The ring nitrogen atom in such a heteroaryl groupwhich carries the group R³², is the ring nitrogen atom in a 5-memberedring such as pyrrole, pyrazole or imidazole to which an exocyclic atomor group such as a hydrogen atom is bonded, and can be present once onlyin a 5-membered aromatic ring just as the hetero ring members O and S.Examples of rings from which such a heteroaryl group can be derived arepyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1,3]oxazole),isoxazole ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazole([1,2]thiazole), pyridine, pyridazine, pyrimidine, pyrazine. In oneembodiment of the invention, a monocyclic, 5-membered or 6-memberedheteroaryl group comprises one hetero ring member which is defined asindicated, and in another embodiment of the invention such a heteroarylgroup is chosen from thiophenyl, thiazolyl and pyridinyl, in anotherembodiment from thiophenyl and pyrazolyl, in another embodiment frompyridinyl, thiophenyl and pyrazolyl, in another embodiment fromthiophenyl and pyridinyl, and in another embodiment it is thiophenyl. Amonocyclic, 5-membered or 6-membered heteroaryl group can be bonded viaany ring carbon atom or, in the case of a 5-membered ring comprising ahetero ring member N(R³²), via a ring nitrogen atom, wherein in thelatter case the bond via which the heteroaryl group is attached to theremainder of the molecule, replaces the group R³². In one embodiment ofthe invention, a monocyclic, 5-membered or 6-membered heteroaryl groupis bonded via a ring carbon atom. For example, a thiophenyl group(thienyl group) can be thiophen-2-yl (2-thienyl) or thiophen-3-yl(3-thienyl), furanyl can be furan-2-yl or furan-3-yl, pyridinyl(pyridyl) can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, pyrazolylcan be 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 2H-pyrazol-3-yl, imidazolylcan be 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl or3H-imidazolyl-4-yl, thiazolyl can be thiazol-2-yl, thiazol-4-yl orthiazol-5-yl.

In substituted monocyclic, 5-membered or 6-membered heteroaryl groups,the substituents can be located in any positions, for example in athiophen-2-yl group or a furan-2-yl group in the 3-position and/or inthe 4-position and/or in the 5-position, in a thiophen-3-yl group or afuran-3-yl group in the 2-position and/or in the 4-position and/or inthe 5-position, in a pyridin-2-yl group in the 3-position and/or in the4-position and/or in the 5-position and/or in the 6-position, in apyridin-3-yl group in the 2-position and/or in the 4-position and/or inthe 5-position and/or in the 6-position, in a pyridin-4-yl group in the2-position and/or in the 3-position and/or in the 5-position and/or inthe 6-position. In one embodiment of the invention, a substitutedmonocyclic, 5-membered or 6-membered heteroaryl group is substituted by1, 2 or 3, for example 1 or 2, identical or different substituents.Generally, besides optionally carrying the substituents indicated in thedefinition of the group, suitable ring nitrogen atoms in a monocyclic,5-membered or 6-membered heteroaryl group representing R²⁴ or thearomatic ring comprising the groups Y and Z which are depicted informula I, for example the nitrogen atom in a pyridinyl group, can alsocarry an oxido substituent —O⁻ and be present as an N-oxide.

The above explanations with respect to monocyclic, 5-membered or6-membered aromatic heterocyclic groups apply correspondingly to thebicyclic aromatic heterocyclic groups discussed below which can occur inthe 3-membered to 10-membered ring representing R²⁴ and which can alsobe designated as a bicyclic heteroaryl group.

The rings of the groups Het¹ can be 4-membered, 5-membered, 6-memberedor 7-membered, for example 4-membered, 5-membered or 6-membered, or4-membered or 5-membered, or 5-membered or 6-membered. The group Het¹can be bonded via any ring carbon atom or ring nitrogen atom. In oneembodiment of the invention, Het¹ is bonded via a ring carbon atom.Examples of the group Het¹ from any one or more of which Het¹ can bechosen, are azetidinyl including azetidin-1-yl, oxetanyl includingoxetan-3-yl, tetrahydrofuranyl including tetrahydrofuran-2-yl andtetrahydrofuran-3-yl, tetrahydrothiophenyl includingtetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl,1-oxo-tetrahydrothiophenyl including 1-oxo-tetrahydrothiophen-2-yl and1-oxo-tetrahydrothiophen-3-yl, 1,1-dioxo-tetrahydrothiophenyl including1,1-dioxo-tetrahydrothiophen-2-yl and 1,1-dioxo-tetrahydrothiophen-3-yl,pyrrolidinyl including pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl, tetrahydropyranyl including tetrahydropyran-2-yl,tetrahydropyran-3-yl and tetrahydropyran-4-yl, tetrahydrothiopyranylincluding tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl andtetrahydrothiopyran-4-yl, piperidinyl including piperidin-1-yl,piperidin-2-yl, piperidin-3-yl and piperidin-4-yl, oxepanyl includingoxepan-2-yl, oxepan-3-yl and oxepan-4-yl, azepanyl includingazepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl, 1,3-dioxolanylincluding 1,3-dioxolan-2-yl and 1,3-dioxolan-4-yl, imidazolidinylincluding imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl,[1,3]oxazolidinyl including[1,3]oxazolidin-2-yl, [1,3]oxazolidin-3-yl,[1,3]oxazolidin-4-yl and [1,3]oxazolidin-5-yl, [1,3]thiazolidinylincluding [1,3]thiazolidin-2-yl, [1,3]thiazolidin-3-yl,[1,3]thiazolidin-4-yl and [1,3]thiazolidin-5-yl, [1,3]dioxanyl including[1,3]dioxan-2-yl, [1,3]dioxan-4-yl and[1,3]dioxan-5-yl, [1,4]dioxanylincluding [1,4]dioxan-2-yl, piperazinyl including piperazin-1-yl andpiperazin-2-yl, morpholinyl including morpholin-2-yl, morpholin-3-yl andmorpholin-4-yl, thiomorpholinyl including thiomorpholin-2-yl,thiomorpholin-3-yl and thiomorpholin-4-yl, 1-oxo-thiomorpholinylincluding 1-oxo-thiomorpholin-2-yl, 1-oxo-thiomorpholin-3-yl and1-oxo-thiomorpholin-4-yl, 1,1-dioxo-thiomorpholinyl including1,1-dioxo-thiomorpholin-2-yl, 1,1-dioxo-thiomorpholin-3-yl and1,1-dioxo-thiomorpholin-4-yl, [1,3]diazepanyl, [1,4]diazepanyl,[1,4]oxazepanyl or [1,4]thiazepanyl. Besides by oxo groups in the ringmembers S(O) and S(O)₂ and alkyl groups representing R⁶⁰, the group Het¹is optionally substituted on ring carbon atoms by one or more, forexample 1, 2, 3, 4 or 5, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2,identical or different substituents as indicated, which can be locatedin any positions.

The 3-membered to 10-membered, monocyclic or bicyclic ring which issaturated or unsaturated and which contains 0, 1 or 2 identical ordifferent hetero ring members chosen from the series consisting of N,N(R³²), O, S, S(O) and S(O)₂, which ring represents R²⁴, can comprise 3,4, 5, 6, 7, 8, 9 or 10 ring members. In one embodiment of the invention,a bicyclic ring representing R²⁴ is fused or bridged. An unsaturatedring can be partially unsaturated, i.e. non-aromatic, and contain, forexample, one or two double bonds within the ring, or it can be aromaticand be a ring such as a benzene ring, for example, and altogether thenumber of double bonds within an unsaturated ring can be one, two,three, four or five. In a bicyclic ring, the two individual rings canindependently of each other be saturated or partially unsaturated oraromatic. In one embodiment of the invention, a 3-membered or 4-memberedring representing R²⁴ is saturated. The 3-membered to 10-membered,monocyclic or bicyclic ring can be a carbocyclic ring, i.e. contain 0(zero) hetero ring members, or a heterocyclic ring in which hetero ringmembers can be present as indicated above. In a bicyclic heterocyclicring one or both individual rings can contain hetero ring members. Incase nitrogen atoms are present as hetero ring members in a bicyclicring, they can also be present at a fusion position or a bridgeheadposition. The free bond via which the ring is bonded to the group R²³,can be located at any suitable ring carbon atom or ring nitrogen atom.In one embodiment of the invention the free bond is located at a ringcarbon atom. In general, besides by oxo groups in the ring members S(O)and S(O)₂ and substituents R³² on ring nitrogen atoms, the 3-membered to10 membered ring is optionally substituted on ring carbon atoms by oneor more, for example 1, 2, 3, 4 or 5, or 1, 2, 3 or 4, or 1, 2 or 3, or1 or 2, identical or different substituents as indicated, which can belocated in any positions.

The 3-membered to 10-membered, monocyclic or bicyclic ring representingR²⁴ comprises (C₃-C₇)-cycloalkyl groups, phenyl groups, monocyclic,5-membered or 6-membered aromatic heterocyclic groups and monocyclic4-membered to 7-membered saturated groups as are comprised by thedefinitions of the group Het¹ referred to above. All these groups thusare examples of the said 3-membered to 10-membered ring, and allexplanations given above with respect to these groups applycorrespondingly to the said 3-membered to 10-membered ring unlessspecified otherwise in the definition of the said 3-membered to10-membered ring. Thus, for example, the substituents in these groupswhen representing the said 3-membered to 10-membered ring, such as in aphenyl group representing the said 3-membered to 10-membered ring, canthen be as is specified in the definition of R²⁴. As further examples ofcyclic groups which are comprised by the said 3-membered to 10-memberedring, (C₅-C₇)-cycloalkenyl groups, naphthalenyl groups and hydrogenatednaphthalenyl groups, indenyl groups and hydrogenated indenyl groups,bicyclic heterocyclic groups, and bicycloalkyl and bicycloalkenyl groupsand hetero analogs thereof may be mentioned.

In a (C₅-C₇)-cycloalkenyl group representing R²⁴, the number of ringcarbon atoms can be 5, 6 or 7. Examples of cycloalkenyl groups arecyclopentenyl including cyclopent-1-enyl, cyclopent-2-enyl andcyclopent-3-enyl, cyclohexyl including cyclohex-1-enyl, cyclohex-2-enyland cyclohex-3-enyl, and cycloheptyl including cyclohept-1-enyl,cyclohept-2-enyl, cyclohept-3-enyl and cyclohept-4-enyl. Cycloalkenylgroups representing R²⁴ can be unsubstituted or substituted as indicatedwith respect to the 3-membered to 10-membered ring representing R²⁴, forexample by one or more, or 1, 2, 3 or 4, or 1, 2 or 3, identical ordifferent (C₁-C₄)-alkyl substituents, for example by methyl groups,which can be located in any positions. Examples of suchalkyl-substituted cycloalkenyl groups are 1-methylcyclopent-2-enyl,1-methylcyclopent-3-enyl, 2,3-dimethylcyclohex-2-enyl and3,4-dimethylcyclohex-3-enyl. Cycloalkenyl groups also are optionallysubstituted by one or more fluorine substituents, i.e., they can beunsubstituted by fluorine and not carry any fluorine substituents, orsubstituted, for example by 1, 2, 3, 4, 5, 6 or 7, or by 1, 2, 3, 4 or5, or by 1, 2, 3 or 4, fluorine substituents. Cycloalkenyl groups canalso be substituted simultaneously by fluorine and alkyl. The fluorineatoms can be located in any positions of the cycloalkenyl group and canalso be located in an alkyl substituent on the cycloalkenyl group.Examples of fluoro-substituted cycloalkyl groups are1-fluorocyclohex-2-enyl, 1-fluorocyclohex-3-enyl and4,4-difluorocyclohex-2-enyl.

Naphthalenyl groups (naphthyl groups) representing R²⁴ can benaphthalen-1-yl (1-naphthyl) and naphthalen-2-yl (2-naphthyl) groups,and are optionally substituted by one or more, for example by 1, 2, 3, 4or 5, or by 1, 2 or 3, for example by 1 or 2, identical or differentsubstituents as indicated above. The substituents in a substitutednaphthalenyl group can be located in any positions, for example in the2-position, 3-position, 4-position, 5-position, 6-position, 7-positionor 8-position in the case of a monosubstituted naphthalen-1-yl group andin the 1-position, 3-position, 4-position, 5-position, 6-position,7-position or 8-position in the case of a monosubstitutednaphthalen-2-yl group. Likewise, in a naphthalenyl group which carriestwo or more substituents, the substituents can be located in the ring towhich the remainder of the molecule is bonded, and/or in the other ring.Examples of hydrogenated naphthalenyl groups representing R²⁴ aredihydronaphthalenyl including 1,4-dihydronaphthalenyl,tetrahydronaphthalenyl including 1,2,3,4-tetrahydronaphthalenyl and5,6,7,8-tetrahydronaphthalenyl, octahydronaphthalenyl including1,2,3,4,5,6,7,8-octahydronaphthalenyl, and decahydronaphthalenyl.Hydrogenated naphthalenyl groups can be bonded to the remainder of themolecule via any ring carbon atom in a saturated or partiallyunsaturated or aromatic ring and are optionally substituted by one ormore, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1or 2, identical or different substituents as indicated above which canbe located in any positions.

Indenyl groups representing R²⁴ can be 1H-inden-1-yl, 1H-inden-2-yl,1H-inden-3-yl, 1H-inden-4-yl, 1H-inden-5-yl, 1H-inden-6-yl or1H-inden-7-yl, for example, and are optionally substituted by one ormore, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1or 2, identical or different substituents as indicated above which canbe located in any positions. Examples of hydrogenated indenyl groupsrepresenting R²⁴ are indanyl (2,3-dihydro-1H-indenyl) andoctahydroindenyl (=Octahydro-1H-indenyl), which can be bonded to theremainder of the molecule via any ring carbon atom in a saturated orpartially unsaturated or aromatic ring, for example via the 1-position,2-position, 4-position or 5-position in the case of an indanyl group,and are optionally substituted by one or more, for example by 1, 2, 3, 4or 5, or by 1, 2 or 3, for example by 1 or 2, identical or differentsubstituents as indicated above which can be located in any positions.

In one embodiment of the invention, bicyclic heterocyclic groupsrepresenting R²⁴ are fused bicyclic groups in which the two rings have abond in common, and can be saturated, partially unsaturated or aromaticas indicated above with respect to the 3-membered to 10-membered ringrepresenting R²⁴ in general. They can contain 1, 2, 3, 4 or 5 doublebonds within the rings. Both of the rings can be saturated, or one ofthe rings can be saturated or partially unsaturated and the other ringpartially unsaturated or aromatic, or both rings can be aromatic, i.e.comprise a cyclic system of six delocalized pi electrons. In oneembodiment of the invention, both rings are aromatic or one of the ringsis aromatic and the other ring is partially unsaturated and comprises atleast one double bond due to the condensation to the aromatic ring. Inone embodiment of the invention, a bicyclic heterocyclic group comprises8, 9 or 10 ring members and two fused 5-membered rings or two fused6-membered rings or a 6-membered ring fused to a 5-membered ring or a7-membered ring fused to a 5-membered ring, in another embodiment 9 or10 ring members and two fused 6-membered rings or a 6-membered ringfused to a 5-membered ring. Hetero ring members can be present in bothrings of a bicyclic heterocyclic group or in one of the rings only andthe other ring contain no hetero ring members. Ring nitrogen atoms canalso be common to both rings. Besides being a hetero ring member in a3-membered to 10-membered rings representing R²⁴ such as saturatedrings, a ring nitrogen atom carrying a group R³² can be the ringnitrogen atom in a fused 5-membered ring in an aromatic bicyclicheterocyclic group, such as in a fused pyrrole, pyrazole or imidazole,to which an exocyclic atom or group is bonded. Examples of rings fromwhich a fused bicyclic heterocyclic group can be derived, are indole,isoindole, benzo[b]thiophene, benzofuran, benzo[1,3]dioxole([1,3]benzodioxole, 1,2-methylenedioxybenzene), benzo[1,3]oxazole,benzo[1,3]thiazole, benzoimidazole, chromane, isochromane,benzo[1,4]dioxane ([1,4]benzodioxane, 1,2-ethylenedioxybenzene),quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline,phthalazine, pyrroloazepines, imidazoazepines, thienothiophenes,thienopyrroles, thienopyridines, naphthyridines, and the respectiverings in which one or some or all of the double bonds are hydrogenated,i.e. replaced with single bonds, such as 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, 2,3-dihydrobenzofuran,1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline,decahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,5,6,7,8-tetrahydroisoquinoline, decahydroisoquinoline, for example. Abicyclic heterocyclic group can be bonded via any ring carbon atom orring nitrogen atom. In one embodiment of the invention, a bicyclicheteroaromatic group is bonded via a ring carbon atom. For example, anindolyl group can be indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl,indol-5-yl, indol-6- or indol-7-yl, a benzoimidazolyl group can be1H-benzoimidazol-1-yl, 1H-benzoimidazol-2-yl, 1H-benzoimidazol-4-yl,1H-benzoimidazol-5-yl, 1H-benzoimidazol-6-yl or 1H-benzoimidazol-7-yl, abenzo[1,4]dioxanyl group can be benzo[1,4]dioxan-2-yl,benzo[1,4]dioxan-5-yl or benzo[1,4]dioxan-6-yl, a quinolinyl group(quinolyl group) can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-5-yl, quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, anisoquinolinyl group can be isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-ylor isoquinolin-8-yl. In a substituted bicyclic heteroaromatic group, thesubstituents can be located in any desired positions such as, forexample, in an indol-2-yl group in the 1-position and/or the 3-positionand/or the 4-position and/or the 5-position and/or the 6-position and/orthe 7-position, in an indol-5-yl group in the 1-position and/or the2-position and/or the 3-position and/or the 4-position and/or the6-position and/or the 7-position, in a 1H-benzoimidazol-2-yl group inthe 1-position and/or the 4-position and/or the 5-position and/or the6-position and/or the 7-position. Generally, besides the substituentsindicated above, a bicyclic heterocyclic group can also carry onsuitable ring nitrogen atoms in aromatic rings, for example the nitrogenatom in a quinolinyl group or isoquinolinyl group, an oxido substituent—O⁻ and be present as an N-oxide.

In one embodiment of the invention, bicycloalkyl and bicycloalkenylgroups representing R²⁴ are bridged 6-membered to 10-membered, inanother embodiment 7-membered to 10-membered and bicyclic groups whichcan contain carbon atoms only as ring members, i.e. they can be derivedfrom carbocyclic bicycloalkanes and bicycloalkenes, or which can alsocontain hetero ring members as indicated above, i.e. they can be derivedfrom the respective heteroanalogous aza-, oxa- and thia-bicycloalkanesand -bicycloalkenes. If they contain hetero ring members, in oneembodiment they contain one hetero ring member, for example one ringmember chosen from the series consisting of N, N(R³²) and O. The heteroring members can be present in any desired positions in the bicyclicsystem including positions in the bridges and, in the case of nitrogenatoms, positions at the bridgeheads. Bicycloalkenyl and their heteroanalogs can contain one or more double bonds within the rings. In oneembodiment of the invention they contain one or two double bonds, inanother embodiment one double bond, within the ring. Bicycloalkyl andbicycloalkenyl can be bonded to the remainder of the molecule via anyring carbon atom or ring nitrogen atom. The free bond can be located inany stereochemical position, for example in an exo position or an endoposition. Bicycloalkyl and bicycloalkenyl and their hetero analogs areoptionally substituted as indicated above, for example by substituentschosen from the series consisting of (C₁-C₄)-alkyl, (O₂—C₅)-alkenyl,HO—, HO—CH₂— (hydroxymethyl-) and oxo, in any positions. Examples ofbicycloalkyl and bicycloalkenyl groups and hetero analogs thereof arenorbornyl (bicyclo[2.2.1]heptyl), bicyclo[3.1.1]heptyl,bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.2]octyl,bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.1]octyl,7-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, bicyclo[2.2.2.]oct-2-en-yl.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, halogen is fluorine, chlorine or bromine, in anotherembodiment fluorine or chlorine, in another embodiment fluorine.

An oxo group, i.e. an oxygen atom which is bonded via a double bond,when bonded to a carbon atom, replaces two hydrogen atoms on the carbonatom of the parent system to which it is bonded. Thus, if a CH₂ group issubstituted by oxo, it becomes a carbonyl group (C(O), C═O). An oxogroup cannot occur as a substituent on a carbon atom in an aromatic ringsuch as in a phenyl group. Similarly, a methylene group which can occuras a substituent on the ring A and in this case is a group CH₂ bondedvia a double bond, replaces two hydrogen atoms on the carbon atom of theparent system to which it is bonded, thus forming the group C═CH₂.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example all enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I, for example in unsubstituted or substituted alkyl groups,can all independently of each other have the S configuration or the Rconfiguration. The invention relates to enantiomers, both thelevorotatory and the dextrorotatory antipode, in enantiomerically pureform and essentially enantiomerically pure form, for example with amolar ratio of the two enantiomers of 99:1 or greater, and in the formof racemates and in the form of mixtures of the two enantiomers in allratios. The invention likewise relates to diastereomers in the form ofpure and essentially pure diastereomers and in the form of mixtures oftwo or more diastereomers in all ratios. The invention also comprisesall cis/trans isomers of the compounds of the formula I in pure form andessentially pure form, for example with a molar ratio of the cis/transisomers of 99:1 or greater, and in the form of mixtures of the cisisomer and the trans isomer in all ratios. Cis/trans isomerism can occurin substituted rings, such as the ring A, and on double bonds, forexample. The preparation of individual stereoisomers, if desired, can becarried out by resolution of a mixture according to customary methods,for example, by chromatography or crystallization, or by use ofstereochemically uniform starting compounds in the synthesis or bystereoselective reactions. Optionally, before a separation ofstereoisomers a derivatization can be carried out. The separation of amixture of stereoisomers can be carried out at the stage of the compoundof the formula I or at the stage of an intermediate in the course of thesynthesis. The invention also comprises all tautomeric forms of thecompounds of the formula I.

Physiologically acceptable salts, including pharmaceutically utilizablesalts, of the compounds of the formula I generally comprise a nontoxicsalt component. They can contain inorganic or organic salt components.Such salts can be formed, for example, from compounds of the formula Iwhich contain an acidic group, for example a carboxylic acid group(hydroxycarbonyl group, HO—C(O)—), and nontoxic inorganic or organicbases. Suitable bases are, for example, alkali metal compounds oralkaline earth metal compounds, such as sodium hydroxide, potassiumhydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia,organic amino compounds and quaternary ammonium hydroxides. Reactions ofcompounds of the formula I with bases for the preparation of the saltsare in general carried out according to customary procedures in asolvent or diluent. Examples of salts of acidic groups thus are sodium,potassium, magnesium or calcium salts or ammonium salts which can alsocarry one or more organic groups on the nitrogen atom. Compounds of theformula I which contain a basic, i.e. protonatable, group, for examplean amino group or a basic heterocycle, can be present in the form oftheir acid addition salts with physiologically acceptable acids, forexample as salt with hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid,p-toluenesulfonic acid, which in general can be prepared from thecompounds of the formula I by reaction with an acid in a solvent ordiluent according to customary procedures. If the compounds of theformula I simultaneously contain an acidic and a basic group in themolecule, the invention also includes internal salts (betaines,zwitterions) in addition to the salt forms mentioned. The presentinvention also comprises all salts of the compounds of the formula Iwhich, because of low physiological tolerability, are not directlysuitable for use as a pharmaceutical, but are suitable as intermediatesfor chemical reactions or for the preparation of physiologicallyacceptable salts, for example by means of anion exchange or cationexchange. The present invention also comprises active metabolites ofcompounds of the formula I and prodrugs of the compounds of the formulaI, i.e. compounds which in vitro may not necessarily exhibitpharmacological activity but which in vivo are converted intopharmacologically active compounds of the formula I, for examplecompounds which are converted by metabolic hydrolysis into a compound ofthe formula I, such as compounds in which a carboxylic acid group ispresent in esterified form or in the form of an amide.

The ring A can be monocyclic, i.e. comprise one ring only, or bicyclic,i.e. comprise two rings which have two or more ring members and one ormore bonds in common and can thus be bridged or fused, or spirocyclic,i.e. comprise two rings which have one ring member in common. The numberof ring members in the ring A can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.In one embodiment of the invention, the ring A is 3-membered to11-membered, in another embodiment 3-membered to 10-membered, in anotherembodiment 3-membered to 8-membered, in another embodiment 3-membered to7-membered, in another embodiment 5-membered to 10-membered, in anotherembodiment 5-membered to 8-membered, in another embodiment 5-membered to7-membered, in another embodiment 6-membered to 8-membered, in anotherembodiment 6-membered or 7-membered. In one embodiment of the invention,a monocyclic ring representing A is 3-membered to 8-membered, in anotherembodiment 3-membered to 7-membered, in another embodiment 5-membered to8-membered, in another embodiment 5-membered to 7-membered, in anotherembodiment 6-membered to 8-membered, in another embodiment 6-membered or7-membered, in another embodiment 3-membered, 6-membered or 7-membered.In one embodiment of the invention, a bicyclic ring representing A is6-membered to 12-membered, in another embodiment 7-membered to12-membered, in another embodiment 6-membered to 10-membered, in anotherembodiment 7-membered to 10-membered, in another embodiment 6-memberedto 8-membered, in another embodiment 7-membered or 8-membered. In oneembodiment of the invention, a spirocyclic ring representing A is7-membered to 12-membered, in another embodiment 8-membered to12-membered, in another embodiment 7-membered to 11-membered, in anotherembodiment 8-membered to 11-membered. In all these embodiments can thenumber of ring members in the ring A have all those values from thegeneral number of ring members, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12,which are comprised by the respective embodiment. In case the ring A isa spiro-fused ring, in one embodiment of the invention comprises thering which does not carry the groups N(R²⁰) and C(O)—R⁵⁰, 3, 4, 5 or 6ring members including the spiro atom, in another embodiment 3, 4 or 5ring members including the spiro atom. In one embodiment of theinvention, the ring A is a monocyclic or bicyclic ring, in anotherembodiment a monocyclic or spirocyclic ring, in another embodiment it isa monocyclic ring, in another embodiment it is a bicyclic ring, inanother embodiment it is a spirocyclic ring, wherein in all theseembodiments the rings are as indicated above or below herein.

The carbon atom in the ring A which carries the two groups N(R²⁰) andC(O)—R⁵⁰, can be present in any ring position which allows for thebinding of two groups. The hetero ring members in the ring A can bepresent in any combination and can be located in any suitable position,wherein generally the two ring members in the ring A which are adjacentto the ring carbon atom carrying the groups N(R²⁰) and C(O)—R⁵⁰ arecarbon atoms, as is also depicted in formula I by the two vertices(corners) in the circumferential line of ring A which, like the vertexin the circumferential line representing the carbon atom which carriesthe two groups N(R²⁰) and C(O)—R⁵⁰, represent carbon atoms as usual insuch structural formulae. In bicyclic rings representing A, the heteroring members can be present in the bridges and, in the case of nitrogenatoms, at the bridgeheads. Likewise as mentioned with respect toheterocyclic rings in the compounds of the formula I in general, in oneembodiment of the invention two hetero ring members from the seriesconsisting of N(R⁰), O and S are not present in adjacent ring positions,in another embodiment two hetero ring members from the series consistingof N(R⁰), O and S are separated by at least two ring carbon atoms, inanother embodiment two hetero ring members are not present in adjacentring positions, in another embodiment two hetero ring members areseparated by at least two ring carbon atoms. In one embodiment of theinvention, the number of hetero ring members in the ring A is 0 or 1, inanother embodiment it is 1, and in another embodiment it is 0, i.e. inthis latter embodiment the ring A is a carbocyclic ring. In oneembodiment of the invention, the hetero ring members in a heterocyclicring representing A are chosen from O, S, S(O) and S(O)₂, in anotherembodiment from S, S(O) and S(O)₂, in another embodiment from S(O) andS(O)₂, in another embodiment from O and S, in another embodiment from Oand N(R⁰), in another embodiment they are O atoms, in another embodimentthey are S atoms, in another embodiment they are N(R⁰ groups. The doublebond which can be present in the ring A, can be located in any suitableposition. In one embodiment of the invention, the ring A is a 3-memberedto 12-membered ring in case it is saturated, and a 5-membered to12-membered ring in case it comprises a double bond, wherein in theseembodiments all other features of the rings are as indicated above orbelow.

In one embodiment of the invention, the ring A is saturated and thusdoes not comprise a double bond in the ring, in another embodiment thering A comprises one double bond.

Examples of rings A from any one or more of which the ring A is chosenin one embodiment of the invention, are (C₃-C₈)-cycloalkane rings,(C₅-C₈)-cycloalkane rings, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, (C₅-C₈)-cycloalkenerings, cyclopent-3-ene wherein the carbon atom carrying the two groupsN(R²⁰) and C(O)—R⁵⁰ is in position 1, cyclohex-3-ene wherein the carbonatom carrying the two groups N(R²⁰) and C(O)—R⁵⁰ is in position 1,cyclohept-3-ene wherein the carbon atom carrying the two groups N(R²⁰)and C(O)—R⁵⁰ is in position 1, cyclohept-4-ene wherein the carbon atomcarrying the two groups N(R²⁰) and C(O)—R⁵⁰ is in position 1,tetrahydrofuran with binding position 3, tetrahydrothiophene and1-oxo-tetrahydrothiophene and 1,1-dioxo-tetrahydrothiophene all withbinding position 3, pyran with binding position 3, pyran with bindingposition 4, tetrahydrothiopyran and 1-oxo-tetrahydrothiopyran and1,1-dioxo-tetrahydrothiopyran all with binding position 3,tetrahydrothiopyran and 1-oxo-tetrahydrothiopyran and1,1-dioxo-tetrahydrothiopyran all with binding position 4, oxepane withbinding position 3, oxepane with binding position 4, thiepane and1-oxo-thiepane and 1,1-dioxo-thiepane all with binding position 3,thiepane and 1-oxo-thiepane and 1,1-dioxo-thiepane all with bindingposition 4, bicyclo[2.2.1]heptane with binding position 2,bicyclo[3.1.1]heptane with binding position 3, bicyclo[3.2.1]octane withbinding position 3, bicyclo[5.1.0]octane with binding position 4,bicyclo[2.2.1]hept-5-ene with binding position2,7-oxabicyclo[2.2.1]heptane with binding position 2, spiro[2.4]heptanewith binding position 5, spiro[2.5]octane with binding position 6,spiro[2,6]nonane with binding position 5, spiro[2.6]nonane with bindingposition 6,1,4-dioxa-spiro[4,4]nonane with binding position7,1,4-dioxa-spiro[4.5]decane with binding position8,1,4-dioxa-spiro[4.6]undecane with binding position 7, or1,4-dioxa-spiro[4.6]undecane with binding position 8, which all areoptionally substituted as indicated above or below including, forexample, substituted cyclohexane rings such as 2-fluoro-cyclohexane,3-fluoro-cyclohexane, 4-fluoro-cyclohexane,4-[(C₁-C₄)-alkyl]-cyclohexane, 4-methyl-cyclohexane,4-ethyl-cyclohexane, 4-propyl-cyclohexane,4-[(C₁-C₄)-alkyl-O]-cyclohexane, 4-methoxy-cyclohexane or4-ethoxy-cyclohexane, wherein in all these substituted cyclohexane ringthe carbon atom carrying the two groups N(R²⁰) and C(O)—R⁵⁰ is inposition 1, and wherein the statement “with binding position” means withrespect to all listed groups that the carbon atom carrying the twogroups N(R²⁰) and C(O)—R⁵⁰ is in the specified position of therespective ring.

The number of the substituents which are optionally present on the ringA, depends on the size and the kind of the ring A and the number ofhetero ring members. In one embodiment of the invention the number ofoptional substituents on ring carbon atoms in ring A is 1, 2, 3 4 or 5,in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, inanother embodiment 1 or 2, in another embodiment 1. In all positions onring carbon atoms in ring A which do not carry a substituent, hydrogenatoms are present. Substituents on the ring A can be present in anysuitable position. In case ring A is a 4-membered to 12-membered ring,in one embodiment of the invention substituents are optionally presentonly on ring carbon atoms which are not adjacent to the carbon atomcarrying the group N(R²⁰) and C(O)—R⁵⁰, but not in the positionsadjacent to the said carbon atom. In one embodiment of the invention,the substituents which are optionally present on carbon atoms in thering A, are chosen from the series consisting of halogen, R¹, R²,(C₂-C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R¹)—,R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—,H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, NC—, oxo and methylene, inanother embodiment from the series consisting of halogen, R¹, R²,(C₂-C₆)-alkenyl, HO—, R¹—C—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—,R¹—N(R¹)—C(O)—, NC—, oxo and methylene, in another embodiment from theseries consisting of halogen, R¹, R², (C₂-C₆)-alkenyl, HO—, R¹—O—,phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—, H₂N—, R¹—NH—,R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—,oxo and methylene, in another embodiment from the series consisting ofhalogen, R¹, R², (C₂-C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—,R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—,R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, oxo and methylene, in another embodimentfrom the series consisting of halogen, R¹, R², (C₂-C₆)-alkenyl, HO—,R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—, HO—C(O)—,R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, oxo and methylene,in another embodiment from the series consisting of halogen, R¹, R²,(C₂-C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—,R¹—N(R¹)—C(O)— and oxo, in another embodiment from the series consistingof halogen, R¹, R², (C₂-C₆)-alkenyl, HO—, R¹—O—,phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—, HO—C(O)—, R¹—O—C(O)—,oxo and methylene, in another embodiment from the series consisting ofhalogen, R¹, R², (C₂-C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—,R¹—C(O)—O—, R¹—S(O)₂—O—, HO—C(O)—, R¹—O—C(O)— and oxo, in anotherembodiment from the series consisting of halogen, R¹, R², HO—, R¹—O—,phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, HO—C(O)—, R¹—O—C(O)—, oxo andmethylene, in another embodiment from the series consisting of halogen,R¹, R², HO—, R¹—O—, R¹—C(O)—O— and oxo, in another embodiment from theseries consisting of halogen, R¹, R², HO—, R¹—O— and oxo, in anotherembodiment from the series consisting of halogen, R¹, R², HO— and R¹—O—,in another embodiment from the series consisting of halogen, R¹, R² andR¹—O—, in another embodiment from the series consisting of halogen, R¹and R², in another embodiment from the series consisting of halogen, R¹,HO— and R¹—O—, in another embodiment from the series consisting ofhalogen, R¹ and R¹—O—, in another embodiment from the series consistingof halogen, HO— and R¹—O—, in another embodiment from the seriesconsisting of halogen and R¹, and in another embodiment the substituentswhich are optionally present on carbon atoms in the ring A aresubstituents R¹, wherein all substituents can be identical or different,and wherein all alkyl, alkenyl and cycloalkyl groups in the substituentson the ring A are optionally substituted by one or more fluorinesubstituents and cycloalkyl groups additionally are optionallysubstituted by one or more (C₁-C₄)-alkyl substituents, as applies ingeneral to alkyl, alkenyl and cycloalkyl groups in the compounds of theformula I. In one embodiment of the invention, an individual carbon atomin the ring A does not carry more than one substituent chosen from theseries consisting of HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, R¹—S(O)_(m), —H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—,R¹—C(O)—N(R¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—,R¹—N(R¹)—S(O)₂— and F₅S—. In one embodiment of the invention, the numberof F₅S— substituents on the ring A is not greater than one. In oneembodiment of the invention, the number of oxo substituents on the ringA is not greater than two, and in another embodiment it is not greaterthan one. In one embodiment of the invention, the number of methylenesubstituents on the ring A is not greater than two, and in anotherembodiment it is not greater than one. In one embodiment of theinvention, halogen substituents on the ring A are fluorine substituents.

In case the ring A is a cyclohexane ring or cycloheptane ring, forexample, the compounds of the formula I can also be represented by theformulae Ia and Ib, respectively,

wherein Y, Z, R²⁰ to R²² and R⁵⁰ are defined as in the compounds of theformula I, R⁷ is defined as the substituents which are optionallypresent in the ring A in the compounds of the formula I, i.e. R⁷ ischosen from the series consisting of halogen, R¹, R², (C₂-C₆)-alkenyl,HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—,R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R¹)—,R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—,H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—,R¹—N(R¹)—S(O)₂—, F₅S—, NC—, oxo and methylene, or from any of the otherseries of substituents indicated herein, for example from the seriesconsisting of halogen, R¹, R², HO—, R¹—O— and oxo, or from the seriesconsisting of halogen and R¹, and the number r can be up to 10 in thecompounds of the formula Ia and up to 12 in the compounds of the formulaIb, such as in case the cyclohexane or cycloheptane ring isperfluorinated. In one embodiment of the invention, the number r in thecompounds of the formulae Ia and Ib is 0, 1, 2, 3, 4 or 5, in anotherembodiment 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, inanother embodiment 0, 1 or 2, in another embodiment 0 or 1, in anotherembodiment the number r is 1, and in another embodiment the number r is0, i.e. in this latter embodiment the cyclohexane ring or cycloheptanering depicted in formulae and Ib does not carry a substituent R⁷ butonly hydrogen atoms. The substituents R⁷ can be present on any of thecarbon atoms of the cyclohexane and cycloheptane ring depicted informulae Ia and Ib.

In the group C(R¹²)═C(R¹³) representing the divalent group Y, the carbonatom carrying the group R¹³ is bonded to the ring carbon atom carryingthe group R²¹ and the carbon atom carrying the group R¹² is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In the groupN═C(R¹⁴), the carbon atom carrying the group R¹⁴ is bonded to the ringcarbon atom carrying the group R²¹ and the nitrogen atom is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In the groupC(R¹⁵)═N, the nitrogen atom is bonded to the ring carbon atom carryingthe group R²¹ and the carbon atom carrying the group R¹⁵ is bonded tothe ring carbon atom carrying the group C(O)—N(R²⁰). In one embodimentof the invention, Y is chosen from the series consisting of S,C(R¹²)═C(R¹³), N═C(R¹⁴) and C(R¹⁵)═N, in another embodiment from theseries consisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N. In one embodiment ofthe invention Y is chosen from the series consisting of S andC(R¹²)═C(R¹³), in another embodiment from the series consisting ofC(R¹²)═C(R¹³) and C(R¹⁵)═N. In another embodiment of the invention, Y isC(R¹²)═C(R¹³). In another embodiment of the invention, Y is C(R¹⁵)═N.

In one embodiment of the invention, the trivalent group Z is C(R¹⁶). Inanother embodiment Z is C(R¹⁶) and Y is chosen from the seriesconsisting of S, C(R¹²)═C(R¹³) and C(R¹⁵)═N. In another embodiment Z isC(R¹⁶) and Y is chosen from the series consisting of S andC(R¹²)═C(R¹³). In another embodiment Z is C(R¹⁶) and Y is chosen fromthe series consisting of C(R¹⁵)═N and C(R¹²)═C(R¹³). In this latterembodiment, the aromatic ring in the compounds of the formula Icomprising the ring members Y and Z is a pyridine ring or a benzenering, respectively, and the compounds of the formula I are compounds ofthe formula Ic or of the formula Id,

wherein A, R¹², R¹³, R¹⁵, R¹⁶, R²⁰ to R²² and R⁵⁰ are defined as in thecompounds of the formula I or have any of their other indicatedmeanings. In one embodiment of the invention the group Z is C(R¹⁶) andthe group Y is S. In another embodiment of the invention the group Z isC(R¹⁶) and the group Y is C(R¹⁵)═N. In another embodiment of theinvention the group Z is C(R¹⁶) and the group Y is C(R¹²)═C(R¹³), i.e.,in this embodiment the compounds of the formula I are compounds of theformula Id.

In one embodiment of the invention, in the compounds of the formula Iathe group Z is C(R¹⁶) and the group Y is C(R¹²)═C(R¹³), i.e., compoundsof this embodiment are compounds of the formula Ie, in anotherembodiment in the compounds of the formula Ib the group Z is C(R¹⁶) andthe group Y is C(R¹²)═C(R¹³), i.e., compounds of this embodiment arecompounds of the formula If, in another embodiment in the compounds ofthe formula Ia the group Z is C(R¹⁶) and the group Y is C(R¹⁵)═N, i.e.,compounds of this embodiment are compounds of the formula Ig, and inanother embodiment in the compounds of the formula Ib the group Z isC(R¹⁶) and the group Y is C(R¹⁵)═N, i.e., compounds of this embodimentare compounds of the formula Ih,

wherein R¹², R¹³, R¹⁵, R¹⁶, R²⁰ to R²² and R⁵⁰ in these compounds aredefined as in the compounds of the formula I or have any of their otherindicated meanings, and R⁷ and r are defined as in the compounds of theformulae Ia and Ib and, like in the compounds of the formulae Ia and Ib,the substituents R⁷ can be present on any of the carbon atoms of thecyclohexane and cycloheptane rings depicted in formulae Ie, If, Ig andIh. All explanations on groups and all definitions and embodimentsspecified above or below with respect to the compounds of the formula Iapply correspondingly to the compounds of all formulae which representsubgroups of the compounds of the formula I, including the compounds ofthe formulae Ia to Ih.

In one embodiment of the invention, R⁰ is chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and methyl. In one embodiment of theinvention, R⁰ is hydrogen. In another embodiment of the invention R⁰ is(C₁-C₄)-alkyl, for example methyl.

In one embodiment of the invention, R¹ is chosen from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and(C₃-C₆)-cycloalkyl-CH₂—, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₄)-cycloalkyl and(C₃-C₄)-cycloalkyl-CH₂—, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl and(C₃-C₄)-cycloalkyl, in another embodiment from the series consisting of(C₁-C₆)-alkyl, in another embodiment from the series consisting of(C₁-C₄)-alkyl, wherein all these groups are all optionally substitutedby one or more fluorine substituents and in the case of cycloalkylgroups by one or more identical or different (C₁-C₄)-alkyl substituents,and thus can also be groups such as fluoromethyl, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, 1-methyl-cyclopropyl or2,2-dimethyl-cyclopropyl, for example.

In one embodiment of the invention, the (C₁-C₄)-alkyl group representingR² is a (C₁-C₃)-alkyl group, in another embodiment a (C₁-C₂)-alkylgroup, in another embodiment a methyl group. In one embodiment of theinvention, the number of substituents HO— and (C₁-C₄)alkyl-O— in R² is1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. In oneembodiment of the invention, an individual carbon atom in R² does notcarry more than one substituent chosen from the series consisting of HO—and (C₁-C₄)alkyl-O—. Examples of R², from any one or more of which R² ischosen in one embodiment of the invention, are hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl,methoxymethyl, propoxymethyl, 2-methoxyethyl or 3-methoxypropyl.

In one embodiment of the invention, R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴,R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the series consisting of (C₁-C₆)-alkyl,(C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of(C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl, which are all optionallysubstituted by one or more identical or different substituents R⁷⁰,wherein in these groups besides any substituents R⁷⁰ one or morefluorine substituents are optionally present and in cycloalkyl groupsone or more (C₁-C₄)-alkyl substituents are optionally present as appliesto alkyl, alkenyl, alkynyl and cycloalkyl groups in general. In oneembodiment of the invention R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷and R⁵⁸, chosen from the series consisting of (C₁-C₆)-alkyl, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl, which are alloptionally substituted by one or more identical or differentsubstituents R⁷⁰. In one embodiment R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ of theinvention, (C₃-C₇)-cycloalkyl groups occurring in R¹¹, and R⁵⁸ are,independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ andR⁵⁸, (C₃-C₆)-cycloalkyl, in another embodiment (C₃-C₄)-cycloalkyl, forexample cyclopropyl, in another embodiment (C₅-C₆)-cycloalkyl, forexample cyclohexyl. In one embodiment of the invention, the number ofsubstituents R⁷⁰ in any of the groups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷and R⁵⁸ is, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴,R⁵⁵, R⁵⁷ and R⁵⁸, 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3,in another embodiment 0, 1 or 2, in another embodiment 0 or 1. In oneembodiment of the invention, any of the groups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴,R⁵⁵, R⁵⁷ and R⁵⁸, independently of each other group R¹¹, R³⁰, R³³, R³⁵,R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, does not carry a substituent R⁷⁰, but merely isoptionally substituted by one or more fluorine substituents and, in thecase of cycloalkyl groups, one or more (C₁-C₄)-alkyl substituents. Inanother embodiment of the invention, any of the groups R¹¹, R³⁰, R³³,R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, independently of each other group R¹¹, R³⁰,R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, does neither carry a substituent R⁷⁰nor fluorine substituents nor, in the case of cycloalkyl groups,(C₁-C₄)-alkyl substituents. As examples of R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵,R⁵⁷ and R⁵⁸ which examplarily carry a hydroxy or alkyl-O— group as asubstituent R⁷⁰, from any one or more of which examples any of thegroups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ is chosen in oneembodiment of the invention, HO—(C₁-C₄)-alkyl-, HO—(C₂-C₃)-alkyl-,HO—CH₂—CH₂—, CH₃—CH(OH)—, HO—CH₂—, (C_(r) C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₁-C₃)-alkyl-O—(C₁-C₃)-alkyl-, (C₁-C₂)-alkyl-O—(C₂-C₃)-alkyl-,(C₁-C₂)-alkyl-O—(C₁-C₂)-alkyl-, CH₃—O—CH₂—CH₂—, (C₁-C₄)-alkyl-O—CH₂—,CH₃—O—CH₂— may be mentioned.

In one embodiment of the invention, R¹⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R¹⁰ ishydrogen. In another embodiment of the invention R¹⁰ is (C₁-C₄)-alkyl,for example methyl.

In case R¹³ or R¹⁴, together with the one of the groups R²¹ and R²²which is not the group of the formula II, forms a chain consisting of 3to 5 chain members of which 0, 1 or 2 chain members are identical ordifferent hetero chain members chosen from the series consisting ofN(R¹⁷), O and S, but two hetero chain members cannot be present inadjacent positions, and the other chain members are identical ordifferent groups C(R¹⁸)(R¹⁸), the group R²² is the group of the formulaII and the group R²¹ forms a chain together with R¹³ or R¹⁴. The formedchain, together with the carbon atom carrying R²¹ and the carbon atomcarrying R¹³ or R¹⁴ forms a 5-membered to 7-membered ring, which isfused to the aromatic ring comprising the groups Y and Z depicted informula I and which has the bond between the group Y and the carbon atomcarrying R²¹ in common with the said ring comprising Y and Z. In oneembodiment of the invention, the said chain consists of 3 to 4 chainmembers and the formed ring thus is 5-membered to 6-membered, and inanother embodiment the said chain consists of 3 chain members and theformed ring thus is 5-membered. The hetero chain members can be presentin any position in the said chain, provided that two hetero chainmembers cannot be present in adjacent positions. If hetero chain membersare present, in one embodiment of the invention one hetero chain memberis present in a terminal position of the said chain, in anotherembodiment one hetero chain member is present in the terminal positionof the said chain which is attached to the carbon atom in the ringcomprising Y and Z depicted in formula I which carries the group R²¹, inanother embodiment one hetero chain member is present in the terminalposition of the said chain which is attached to the carbon atom in thegroup CR¹²═CR¹³ or the group N═CR¹⁴ representing Y which carries thegroup R¹³ or R¹⁴, respectively, in another embodiment two hetero chainmembers are present in the two terminal positions of the said chainwhich are attached to the carbon atom in the ring comprising Y and Zdepicted in formula I which carries the group R²¹, and to the carbonatom in the group CR¹²═CR¹³ or the group N═CR¹⁴ representing Y whichcarries the group R¹³ or R¹⁴, respectively. In one embodiment of theinvention, 0 (zero) hetero chain members are present in the said chain,in another embodiment 0 or 1 hetero chain members are present, inanother embodiment 1 or 2 hetero chain members are present, and inanother embodiment 2 hetero chain members are present. In one embodimentof the invention, hetero chain members in the said chain are chosen fromN(R¹⁷) and o, in another embodiment from O and S, and in anotherembodiment they are O (oxygen atoms). Examples of chains formed by R¹³or R¹⁴ together with the one of the groups R²¹ and R²² which is not thegroup of the formula II, from any one or more of which the said chain ischosen in one embodiment of the invention, are —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —O—CH₂—CH₂— and—O—CH₂—CH₂—CH₂— wherein in the latter two chains the oxygen atom isattached to the carbon atom in the group CR¹²═CR¹³ or the group N═CR¹⁴representing Y which carries the group R¹³ or R¹⁴, respectively,—CH₂—CH₂—O— and —CH₂—CH₂—CH₂—O— wherein in the latter two chains theoxygen atom is attached to the carbon atom in the ring comprising Y andZ depicted in formula I which carries the group R²¹, —CH₂—O—CH₂—,—O—C(R¹⁸)(R¹⁸)—O— including —O—CH₂—O—, —O—CF₂—O— and —O—C(CH₃)₂—O—,—O—C(R¹⁸)(R¹⁸)—C(R¹⁸)(R¹⁸)—O—including —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—,or —N(CH₃)—CH₂—CH₂—O— wherein in the latter chain the nitrogen atom isattached to the carbon atom in the group CR¹²═CR¹³ or the group N═CR¹⁴representing Y which carries the group R¹³ or R¹⁴, respectively.

In one embodiment of the invention, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,H₂N—, (C₁-C₄)-alkyl-NH—, (C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)- and NC—, inanother embodiment from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, H₂N—, (C₁-C₄)-alkyl-NH—,(C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)- and NC—, in another embodiment from theseries consisting of hydrogen, halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhydrogen, halogen and (C₁-C₄)-alkyl-O—, in another embodiment from theseries consisting of hydrogen and halogen, or in all these embodimentsR¹³ or R¹⁴, together with the one of the groups R²¹ and R²² which is notthe group of the formula II, forms a chain consisting of 3 to 5 chainmembers of which 0, 1 or 2 chain members are identical or differenthetero chain members chosen from the series consisting of N(R¹⁷), O andS, but two hetero chain members cannot be present in adjacent positions,and the other chain members are identical or different groupsC(R¹⁸)(R¹⁸). In one embodiment of the invention, R¹² and R¹³ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of hydrogen, halogen and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhydrogen and halogen, in another embodiment from the series consistingof hydrogen, chlorine and fluorine, in another embodiment from theseries consisting of hydrogen and fluorine, or in all these embodimentsR¹³, together with the one of the groups R²¹ and R²² which is not thegroup of the formula II, forms a chain consisting of 3 to 5 chainmembers of which 0, 1 or 2 chain members are identical or differenthetero chain members chosen from the series consisting of N(R¹⁷), O andS, but two hetero chain members cannot be present in adjacent positions,and the other chain members are identical or different groupsC(R¹⁸)(R¹⁸). In one embodiment of the invention, R¹² and R¹³ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of hydrogen, halogen and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhydrogen and halogen, in another embodiment from the series consistingof hydrogen, chlorine and fluorine, in another embodiment from theseries consisting of hydrogen and fluorine. In one embodiment of theinvention, R¹² is chosen from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment fromthe series consisting of hydrogen, halogen and (C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of hydrogen and halogen,in another embodiment from the series consisting of hydrogen, chlorineand fluorine, in another embodiment from the series consisting ofhydrogen and fluorine, and R¹³, together with the one of the groups R²¹and R²² which is not the group of the formula II, forms a chainconsisting of 3 to 5 chain members of which 0, 1 or 2 chain members areidentical or different hetero chain members chosen from the seriesconsisting of N(R¹⁷), O and S, but two hetero chain members cannot bepresent in adjacent positions, and the other chain members are identicalor different groups C(R¹⁸)(R¹⁸). In one embodiment of the invention, R¹²is hydrogen and R¹³ is fluorine, or R¹² is fluorine and R¹³ is hydrogen.In another embodiment R¹² and R¹³ are hydrogen. In one embodiment of theinvention, R¹⁴ and R¹⁵ are independently of each other chosen from theseries consisting of hydrogen, halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhydrogen, halogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and halogen, in another embodiment fromthe series consisting of hydrogen, chlorine and fluorine. In anotherembodiment of the invention, R¹⁴ and R¹⁵ are hydrogen. In one embodimentof the invention, R¹⁶ is chosen from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment fromthe series consisting of hydrogen, halogen and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen and halogen, inanother embodiment from the series consisting of hydrogen, chlorine andfluorine. In another embodiment of the invention, R¹⁶ is hydrogen.

In one embodiment of the invention, R¹⁷ and R²⁵ are independently ofeach other chosen from the series consisting of hydrogen and methyl, inanother embodiment they are hydrogen. In another embodiment of theinvention, R¹⁷ and R²⁵ are independently of each other chosen from theseries consisting of (C₁-C₄)-alkyl, and in another embodiment they aremethyl.

In case two groups R¹⁸ bonded to the same carbon atom, together with thecarbon atom carrying them, form a 3-membered to 6-membered cycloalkanering, the formed cycloalkane ring is spiro-fused to the ring which isoptionally formed by R¹³ or R¹⁴ together with the one of the groups R²¹and R²² which is not the group of the formula II, and the carbon atomcarrying R²¹ and the carbon atom carrying R¹³ or R¹⁴. In one embodimentof the invention, the cycloalkane ring formed by two of the groups R¹⁸is 3-membered to 5-membered, in another embodiment it is 3-membered or4-membered, in another embodiment it is 3-membered, i.e. in this latterembodiment a cyclopropane ring is formed. In one embodiment of theinvention, R¹⁸, independently of each other group R¹⁸, is chosen fromthe series consisting of hydrogen, fluorine and (C₁-C₂)-alkyl, inanother embodiment from the series consisting of hydrogen, fluorine andmethyl, in another embodiment from the series consisting of hydrogen andfluorine, and in another embodiment the groups R¹⁸ are hydrogen, or inall these embodiments two of the groups R¹⁸ bonded to the same carbonatom, together with the carbon atom carrying them, form a 3-membered to6-membered cycloalkane ring which is optionally substituted asindicated. In one embodiment of the invention, R¹⁸, independently ofeach other group R¹⁸, is chosen from the series consisting of hydrogen,fluorine and (C₁-C₂)-alkyl, in another embodiment from the seriesconsisting of hydrogen, fluorine and methyl, in another embodiment fromthe series consisting of hydrogen and fluorine, and in anotherembodiment the groups R¹⁸ are hydrogen. In one embodiment of theinvention, not more than one cycloalkane ring which is formed by two ofthe groups R¹⁸ bonded to the same carbon atom together with the carbonatom carrying them, is present in the compounds of the formula I. In oneembodiment of the invention, the number of substituents chosen from theseries consisting of fluorine and (C₁-C₄)-alkyl, which are optionallypresent on a cycloalkane ring formed by two of the groups R¹⁸ bonded tothe same carbon atom together with the carbon atom carrying them, is 1,2, 3 or 4, in another embodiment it is 1, 2 or 3, in another embodimentit is 1 or 2, and in another embodiment such a cycloalkane ring does notcarry any substituents, i.e. in this latter embodiment it isunsubstituted. In one embodiment of the invention, the substituentswhich are optionally present on a cycloalkane ring formed by two of thegroups R¹⁸ bonded to the same carbon atom together with the carbon atomcarrying them, are chosen from fluorine and methyl, and in anotherembodiment they are fluorine substituents.

In one embodiment of the invention, R²⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R²⁰ ishydrogen. In another embodiment R²⁰ is (C₁-C₄)-alkyl, for examplemethyl.

In one embodiment of the invention the group R²¹ is the one of thegroups R²¹ and R²² which is a group of the formula II, i.e. a group ofthe formula R²⁴—R²³— which is bonded to the remainder of the moleculethrough the moiety R²³ as is symbolized with respect to this group andin general by a terminal hyphen representing the free bond, and thegroup R²² is chosen from the series consisting of hydrogen, halogen,R³⁰, —HO—, R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—,R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—,R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—, H₂N—C(O)—,R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹. In another embodiment, the groupR²² is the one of the groups R²¹ and R²² which is a group of the formulaII and the group R²¹ is chosen from the series consisting of hydrogen,halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—,H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—,R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—,H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹, or together with R¹³ or R¹⁴ formsa chain as specified in the definition of R¹³ and R¹⁴ .

In one embodiment of the invention, the one of the groups R²¹ and R²²which is not a group of the formula II, is chosen from the seriesconsisting of hydrogen, halogen, R³⁰, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—, NC—and Het¹, in another embodiment from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, H₂N—,(C₁-C₄)-alkyl-NH—, di((C₁-C₄)-alkyl)N—, (C₁-C₄)-alkyl-C(O)—, Het¹ andNC—, in another embodiment from the series consisting of hydrogen,halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—,(C₁-C₄)-alkyl-C(O)—, Het¹ and NC—, in another embodiment from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-C(O)— and Het¹, in anotherembodiment from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-C(O)— and Het¹, in another embodiment from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— and Het¹, in another embodiment fromthe series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,HO—(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-C(O)— and Het¹, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-C(O)— and Het¹, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— and Het¹, in another embodiment fromthe series consisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—and (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, in another embodiment from theseries consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-C(O)— and Het¹, inanother embodiment from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— and Het¹, inanother embodiment from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,HO—(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-C(O)— and Het¹, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and(C₁-C₄)-alkyl-C(O)—, in another embodiment from the series consisting of(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment from theseries consisting of (C₁-C₄)-alkyl-O—, or in all these embodimentstogether with R¹³ or R¹⁴ forms a chain as specified in the definition ofR¹³ and R¹⁴. In one embodiment of the invention, the one of the groupsR²¹ and R²² which is not a group of the formula II, is chosen from theseries consisting of (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—. In anotherembodiment, the one of the groups R²¹ and R²² which is not a group ofthe formula II, is (C₁-C₄)-alkyl-O—, for example methoxy or ethoxy.

In one embodiment of the invention, in case the group R²¹ is the one ofthe groups R²¹ and R²² which is a group of the formula II, the group R²²is chosen from the series consisting of (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—, and in another embodiment it is (C₁-C₄)-alkyl-O—, andin case the group R²² is the one of the groups R²¹ and R²² which is thegroup of the formula II, the group R²¹ is chosen from the seriesconsisting of hydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—,R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—,R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—,R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹, or together withR¹³ or R¹⁴ forms a chain as specified in the definition of R¹³ and R¹⁴,or is defined as in any of the embodiments or other definitions of R²¹specified herein.

The chain members in a chain representing R²³ are connected to eachother by single bonds. The number of chain members in a chainrepresenting R²³ can be 1, 2, 3, 4 or 5. In one embodiment of theinvention, the divalent group R²³ is a direct bond, i.e. the group R²⁴is directly bonded to the ring comprising the groups Y and Z which isdepicted in formula I. In another embodiment R²³ is a direct bond or achain consisting of 1, 2, 3 or 4 chain members. In another embodimentR²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members,in another embodiment a direct bond or a chain consisting of 2 or 3chain members, in another embodiment a direct bond or a chain consistingof 3 chain members, wherein in these embodiments the chain members aredefined as above or below. In another embodiment R²³ is a chainconsisting of 1, 2, 3, 4 or 5 chain members, in another embodiment achain consisting of 1, 2, 3 or 4 chain members, in another embodiment achain consisting of 2, 3 or 4 chain members, in another embodiment achain consisting of 2 or 3 chain members, in another embodiment a chainconsisting of 3 chain members, wherein in these embodiments the chainmembers are defined as above or below. In one embodiment of theinvention, zero or one of the chain members in a chain representing R²³are hetero chain members, in another embodiment one of the chain membersin a chain representing R²³ is a hetero chain member, and in anotherembodiment zero of the chain members in a chain representing R²³ is ahetero chain member, wherein in these embodiments the hetero chainmembers are defined as above or below. In one embodiment of theinvention, the hetero chain members in a chain representing R²³ arechosen from the series consisting of N(R²⁵), O, S and S(O)₂. In anotherembodiment of the invention, the hetero chain members in a chainrepresenting R²³ are chosen from the series consisting of N(R²⁵), O andS, in another embodiment from the series consisting of N(R²⁵) and O, inanother embodiment from the series consisting of O and S, in anotherembodiment from the series consisting of N(R²⁵), O and S(O)₂, in anotherembodiment from the series consisting of N(R²⁵) and S(O)₂, in anotherembodiment from the series consisting of O and S(O)₂. In anotherembodiment of the invention, the hetero chain members which can bepresent in a chain representing R²³, are O (oxygen), and in anotherembodiment the hetero chain members which can be present in a chainrepresenting R²³, are S. In another embodiment of the invention, zero orone hetero chain member is present in a chain representing R²³ which isO (oxygen), and in another embodiment one hetero chain member is presentwhich is O. In another embodiment of the invention, zero or one heterochain member is present in a chain representing R²³ which is S, and inanother embodiment one hetero chain member is present which is S.

Hetero chain members in a chain representing R²³ can be present in anypositions of the chain provided that the resulting moiety complies withthe prerequisites specified above with respect to R²³ and the compoundsof the invention in general. Hetero chain members can be present in anyone of the terminal positions of the chain or in both terminal positionsof the chain, and can thus be directly bonded to the group R²⁴ and/orthe ring comprising the groups Y and Z which is depicted in formula I,and/or they can be present inside the chain. In case one or two heterochain members are present in a chain representing R²³, in one embodimentof the invention at least one of the terminal chain members is a heterochain member, and in another embodiment the terminal chain member whichis bonded to the group R²⁴ is a hetero chain member, and in anotherembodiment the terminal chain member which is bonded to the ringcomprising the groups Y and Z is a hetero chain member. In oneembodiment of the invention, one of the chain members in a chainrepresenting R²³ is a hetero chain member and this hetero chain memberis the terminal chain member bonded to the group R²⁴. In anotherembodiment, one of the chain members in a chain representing R²³ is ahetero chain member and this hetero chain member is the terminal chainmember bonded to the ring comprising the groups Y and Z which isdepicted in formula I.

In one embodiment of the invention R²³ is chosen from a direct bond andfrom any one or more of the chains which are present in the followingexamples of groups of the formula II, which groups are bonded to thering comprising the groups Y and Z which is depicted in formula I by thefree bond represented by the terminal hyphen, and from which groups ofthe formula II the groups R²³ themselves are obtained by removing thegroup R²⁴:

-   R²⁴—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—-   R²⁴—C(R²⁶)(R²⁶)—O—, R²⁴, —C(R²⁶)(R²⁶)—S—,-   R²⁴—C(R²⁶)(R²⁶)—N(R²⁵)—, R²⁴—S(O)₂—O—,-   R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—,    R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—O—,-   R²⁴—O—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—O—C(R²⁶)(R²⁶)—-   R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—S—, R²⁴—C(R²⁶)(R²⁶)—S—C(R²⁶)(R²⁶)—-   R²⁴—S—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—, R²⁴—C(R²⁶)(R²⁶)—C(R²⁶)(R²⁶)—N(R²⁵)—,    wherein in these groups of the formula II the groups R²⁴, R²⁵ and    R²⁶ are defined as above or below.

In one embodiment of the invention, a 3-membered to 10-membered,monocyclic or bicyclic ring representing R²⁴ is a monocyclic ring, whichis all optionally substituted as indicated above or below. In oneembodiment of the invention, a monocyclic ring representing R²⁴ is3-membered to 7-membered, in another embodiment 3-membered or 5-memberedto 7-membered, in another embodiment 3-membered, 5-membered or6-membered, in another embodiment 5-membered or 6-membered, in anotherembodiment 6-membered, which rings are all optionally substituted asindicated above or below. In one embodiment of the invention, a bicyclicring representing R²⁴ is 7-membered to 10-membered which is optionallysubstituted as indicated above or below. In one embodiment of theinvention, a ring representing R²⁴ is a saturated ring or an unsaturatedring including a partially unsaturated, i.e. non-aromatic, ring whichcontains zero, one, two or three, for example zero, one or two, doublebonds, within the ring, or an aromatic ring, which rings are alloptionally substituted as indicated above or below. In anotherembodiment, a ring representing R²⁴ is a saturated ring or a partiallyunsaturated ring which contains zero, one, two or three, for examplezero, one or two, double bonds within the ring, which rings are alloptionally substituted as indicated above or below. In anotherembodiment of the invention, a ring representing R²⁴ is an aromaticring, in another embodiment an aromatic ring chosen from benzene,aromatic 5-membered and 6-membered monocyclic heterocycles, naphthaleneand aromatic 9-membered and 10-membered bicyclic heterocycles, inanother embodiment an aromatic ring chosen from benzene and aromatic5-membered and 6-membered monocyclic heterocycles, in another embodimentan aromatic ring chosen from benzene and thiophene, which rings are alloptionally substituted as indicated above or below. In anotherembodiment, a ring representing R²⁴ is a benzene ring which isoptionally substituted as indicated above or below, i.e. by thesubstituents specified above or below with respect to the 3-membered to10-membered ring representing R²⁴. In terms of residues, in this latterembodiment R²⁴ is a phenyl group which is optionally substituted asindicated above or below, i.e. by the substituents specified above orbelow with respect to the 3-membered to 10-membered ring representingR²⁴.

In one embodiment of the invention, the number of hetero ring memberswhich can be present in a saturated 3-membered to 10-membered ringrepresenting R²⁴ is 0, in another embodiment it is 1. In one embodimentof the invention, the number of hetero ring members which can be presentin an unsaturated 3-membered to 10-membered ring representing R²⁴ is 0or 1, and in another embodiment it is 1 or 2, in another embodiment itis 1, and in another embodiment the number of hetero ring members is 0(zero), i.e., in this latter embodiment a 3-membered to 10-membered ringrepresenting R²⁴ is a carbocyclic ring, which rings are all optionallysubstituted as indicated above or below. In one embodiment of theinvention, the hetero ring members which can be present in a 3-memberedto 10-membered ring representing R²⁴ are chosen from N, N(R³²), O, S andS(O)₂, in another embodiment from N, N(R³²), O and S, in anotherembodiment from N, O and S, in another embodiment from N(R³²), O and S,in another embodiment from N and S, in another embodiment they are N(nitrogen), and in another embodiment they are S (sulfur).

In one embodiment of the invention, the number of substituents which areoptionally present on ring carbon atoms in a 3-membered to 10-memberedring representing R²⁴ is 1, 2, 3, 4, or 5, in another embodiment thenumber of substituents which are optionally present on ring carbon atomsis 1, 2, 3 or 4, in another embodiment the number of substituents whichare optionally present on ring carbon atoms is 1, 2 or 3, in anotherembodiment the number of substituents which are optionally present onring carbon atoms is 1 or 2, and in another embodiment the number ofsubstituents which are optionally present on ring carbon atoms is 1.

In one embodiment of the invention, the substituents which areoptionally present on ring carbon atoms in a 3-membered to 10-memberedring representing R²⁴, including a benzene ring or a phenyl group,respectively, representing R²⁴, are chosen from the series consisting ofhalogen, R³³, oxetanyl, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—,R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—,R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC— and oxo, in another embodiment fromthe series consisting of halogen, R³³, oxetanyl, HO—, R³³—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—,R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—,R³³—NH—S(O)₂—N(R⁷¹)—, R³³—N(R³³)—S(O)₂—N(R⁷¹)—, HO—C(O)—, R³³—O—C(O)—,H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodimentfrom the series consisting of halogen, R³³, oxetanyl, HO—, R³³—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—,H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—, HO—C(O)—,R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, inanother embodiment from the series consisting of halogen, R³³, oxetanyl,HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—S(O)₂—NH—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—, R³³—N(R³³)—S(O)₂—NH—,H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodimentfrom the series consisting of halogen, R³³, oxetanyl, HO—, R³³—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—,H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodimentfrom the series consisting of halogen, R³³, oxetanyl, HO—, R³³—O—,R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—,R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodiment from theseries consisting of halogen, R³³, oxetanyl, HO—, R³³—O—, R³³—S(O)_(m)—,R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—, R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—,H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, in another embodimentfrom the series consisting of halogen, R³³, oxetanyl, HO—, R³³—O—,R³³—S(O)_(m)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—, H₂N—C(O)—, R³³—NH—C(O)—,R³³—N(R³³)—C(O)— and NC—, in another embodiment from the seriesconsisting of halogen, R³³, oxetanyl, HO—, R³³—O—, R³³—C(O)—NH—,R³³—S(O)₂—NH—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—, inanother embodiment from the series consisting of halogen, R³³, oxetanyl,R³³—O—, R³³—C(O)—NH—, R³³—S(O)₂—NH—, H₂N—C(O)—, R³³—NH—C(O)—,R³³—N(R³³)—C(O)— and NC—, in another embodiment from the seriesconsisting of halogen, R³³, oxetanyl, R³³—O— and NC—, in anotherembodiment from the series consisting of halogen, R³³, oxetanyl, andR³³—O—, in another embodiment from the series consisting of halogen, R³³and oxetanyl, in another embodiment from the series consisting ofhalogen, R³³, R³³—O— and NC—, in another embodiment from the seriesconsisting of halogen, R³³, and R³³—O—, in another embodiment from theseries consisting of halogen and R³³, wherein in all these embodimentsR³³ and R⁷¹ are defined as indicated above or below and R³³ isoptionally substituted by one or more identical or differentsubstituents R⁷⁰. In one embodiment of the invention, the groups R³³ inthese substituents on a ring representing R²⁴ are independently of eachother chosen from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl-CH₂—, in another embodimentfrom the series consisting of (C₁-C₆)-alkyl, cyclopropyl andcyclopropyl-CH₂—, for example from the series consisting of(C₁-C₆)-alkyl, in another embodiment from the series consisting of(C₁-C₄)-alkyl, cyclopropyl and cyclopropyl-CH₂—, for example from theseries consisting of (C₁-C₄)-alkyl. In one embodiment of the invention,the number of substituents R⁷⁰, which are optionally present in thesegroups R³³ besides any fluorine substituents and, in the case ofcycloalkyl groups, any (C₁-C₄)-alkyl substituents, is independently ofeach other 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in anotherembodiment 0 or 1, in another embodiment 0. In one embodiment of theinvention, the substituents R⁷⁰ in these groups R³³ are independently ofeach other chosen from the series consisting of HO—, R⁷¹—O—,R⁷¹—C(O)—O—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—,R⁷¹—S(O)₂—NH— and R⁷¹—S(O)₂—N(R⁷¹)—, in another embodiment from theseries consisting of HO—, R⁷¹—C(O)—O—, H₂N—, R⁷¹—C(O)—NH— andR⁷¹—S(O)₂—NH—, in another embodiment from the series consisting of HO—,R⁷¹—C(O)—O— and R⁷¹—C(O)—NH—, in another embodiment from the seriesconsisting of HO— and R⁷¹—C(O)—NH—, in another embodiment from theseries consisting of HO— and R⁷¹—O—, and in another embodiment of theinvention substituents R⁷⁰ in these groups R³³ are HO—. In oneembodiment of the invention, the groups R⁷¹ present in these groups R³³are independently of each other chosen from the series consisting of(C₁-C₄)-alkyl, cyclopropyl and cyclopropyl-CH₂—, in another embodimentfrom the series consisting of (C₁-C₄)-alkyl and cyclopropyl, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl. In oneembodiment of the invention, the number of nitro substituents (O₂N—) onthe ring R²⁴ is not greater than two, in another embodiment not greaterthan one. In one embodiment of the invention, the total number of nitrogroups in a compound of the formula I is not greater than two. In oneembodiment of the invention, R²⁴ is a benzene ring or a thiophene ring,for example a benzene ring, or, in terms of the respective residues, R²⁴is a phenyl group or a thiophenyl (thienyl) group, for example a phenylgroup, which are all optionally substituted as indicated afore.

Examples of specific residues of benzene and thiophene rings, i.e. ofspecific phenyl and thiophenyl groups, representing R²⁴, from any one ormore of which examples the group R²⁴ is chosen in one embodiment of theinvention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl,2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl,2,5-dichloro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl,3-methyl-phenyl (m-tolyl), 3-ethyl-phenyl, 3-isopropyl-phenyl,3-cyclopropyl-phenyl, 3-tert-butyl-phenyl, 3-trifluoromethyl-phenyl,3-(2-hydroxyethyl)-phenyl, 3-(2-hydroxy-2-methyl-propyl)-phenyl,3-(2-acetylaminoethyl)-phenyl, 2-fluoro-5-methyl-phenyl,3-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl,5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl,2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,5-fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl,5-chloro-2-trifluoromethyl-phenyl, 5-chloro-3-trifluoromethyl-phenyl,3-ethoxy-phenyl, 2-propoxy-phenyl, 3-isopropoxy-phenyl,3-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl,5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl,5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl,4-methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl,3-methylsulfanyl-phenyl, 3-ethylsulfanyl-phenyl,3-trifluoromethylsulfanyl-phenyl, 3-ethanesulfonyl-phenyl,3-acetylamino-phenyl, 3-methanesulfonylamino-phenyl,3-dimethylaminosulfonylamino-phenyl, 3-cyano-phenyl, 2-thienyl,3-thienyl, 4-methyl-2-thienyl, 5-methyl-3-thienyl.

In one embodiment of the invention, R²⁶, independently of each othergroup R²⁶, is chosen from the series consisting of hydrogen, fluorine,methyl and HO—, in another embodiment from the series consisting ofhydrogen, fluorine and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen, fluorine and methyl, in anotherembodiment from the series consisting of hydrogen and fluorine, inanother embodiment from the series consisting of hydrogen and methyl,and in another embodiment R²⁶ is hydrogen, or in all these embodimentstwo groups R²⁶ bonded to the same carbon atom together are oxo, or twoof the groups R²⁶ or one group R²⁵ and one group R²⁶, together with thecomprised chain members, form a 3-membered 5 to 7-membered monocyclicring which is saturated and contains 0, 1 or 2 identical or differenthetero ring members chosen from the series consisting of N, N(R³⁴), O,S, S(O) and S(O)₂, which ring is optionally substituted on ring carbonatoms by one or more identical or different substituents chosen from theseries consisting of fluorine and (C₁-C₄)-alkyl. In another embodimentof the invention, R²⁶, independently of each other group R²⁶, is chosenfrom the series consisting of hydrogen, fluorine, methyl and HO—, inanother embodiment from the series consisting of hydrogen, fluorine and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen, fluorine and methyl, in another embodiment from the seriesconsisting of hydrogen and fluorine, in another embodiment from theseries consisting of hydrogen and methyl, and in another embodiment R²⁶is hydrogen, or in all these embodiments two of the groups R²⁶ or onegroup R²⁵ and one group R²⁶, together with the comprised chain members,form a 3-membered to 7-membered monocyclic ring which is saturated andcontains 0, 1 or 2 identical or different hetero ring members chosenfrom the series consisting of N, N(R³⁴), O, S, S(O) and S(O)₂, whichring is optionally substituted on ring carbon atoms by one or moreidentical or different substituents chosen from the series consisting offluorine and (C₁-C₄)-alkyl. In another embodiment of the invention, R²⁶,independently of each other group R²⁶, is chosen from the seriesconsisting of hydrogen, fluorine, methyl and HO—, in another embodimentfrom the series consisting of hydrogen, fluorine and (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen, fluorine andmethyl, in another embodiment from the series consisting of hydrogen andfluorine, in another embodiment from the series consisting of hydrogenand methyl, and in another embodiment all groups R²⁶ are hydrogen.

In one embodiment of the invention, the number of groups R²⁶ in a chainrepresenting R²³ which are HO—, is zero, one or two, in anotherembodiment zero or one, in another embodiment zero, in anotherembodiment one. In one embodiment of the invention, a HO— grouprepresenting R²⁶ is not present on a carbon atom which is adjacent to ahetero chain member in a chain representing R²³. In one embodiment ofthe invention the number of groups R²⁶ in a chain representing R²³ whichare (C₁-C₄)-alkyl such as methyl, is zero, one or two, in anotherembodiment zero or one, in another embodiment zero, in anotherembodiment one, in another embodiment two. In one embodiment of theinvention the number of groups R²⁶ in a chain representing R²³ which arefluorine, is zero, one, two, three or four, in another embodiment zero,one, two or three, in another embodiment zero, one or two, in anotherembodiment zero or one, in another embodiment zero, in anotherembodiment one, in another embodiment two. In one embodiment of theinvention, the number of oxo substituents in a chain representing R²³which are formed by two groups R²⁶ bonded to the same carbon atom, iszero, one or two, in another embodiment zero or one, in anotherembodiment zero, in another embodiment one. In one embodiment of theinvention, an oxo substituent in a chain representing R²³ is not presenton a carbon atom which is adjacent to a hetero chain member chosen fromthe series consisting of S(O) and S(O)₂, in another embodiment from theseries consisting of S, S(O) and S(O)₂, in another embodiment from theseries consisting of O, S, S(O) and S(O)₂.

In one embodiment of the invention, the number of rings which are formedby two of the groups R²⁶ or one group R²⁵ and one group R²⁶, togetherwith the comprised chain members, is zero, one or two, in anotherembodiment zero or one, in another embodiment one, in another embodimentzero. In one embodiment of the invention a ring formed by two of thegroups R²⁶ or one group R²⁵ and one group R²⁶, together with thecomprised chain members, is a 3-membered, 4-membered, 5-membered or6-membered ring, in another embodiment a 3-membered, 5-membered or6-membered ring, in another embodiment a 3-membered ring, in anotherembodiment a 5-membered or 6-membered ring. In one embodiment of theinvention, it is possible for two of the groups R²⁶, together with thecomprised chain members, to form a ring, but not for one group R²⁵ andone group R²⁶. In one embodiment of the invention the number of chainmembers which is comprised by a ring formed by two of the groups R²⁶ orone group R²⁵ and one group R²⁶, is one, two, three or four, in anotherembodiment it is one, two or three, in another embodiment it is one ortwo, in another embodiment it is one. In case such ring comprises onlyone chain member, the two of the groups R²⁶ forming the ring are bondedto the same carbon atom in the chain and the said one chain member isthe carbon atom carrying the two groups R²⁶. Examples of rings, whichare formed by two groups R²⁶ bonded to the same carbon atom and the onecomprised chain member, are cycloalkane rings such as cyclopropane,cyclobutane, cyclopentane or cyclohexane, and heterocyclic rings such astetrahydrothiophene, tetrahydrothiopyran, oxetane, tetrahydrofuran,tetrahydropyran, azetidine, pyrrolidine or piperidine, for examplecyclopropane, which carry any adjacent chain members of a chainrepresenting R²³ and/or the group R²⁴ and/or the ring comprising thegroups Y and Z which is depicted in formula I, on the same ring carbonatom, and which rings can all be substituted as indicated. In case aring formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶,together with the comprised chain members, comprises two chain members,the two groups R²⁶ forming the ring are bonded to two adjacent carbonatoms in the chain or the one group R²⁶ is bonded to a carbon atom whichis adjacent to the group N(R²⁵), respectively. Examples of rings, whichare formed in such case, are likewise cycloalkane rings such ascyclopropane, cyclobutane, cyclopentane or cyclohexane, and heterocyclicrings such as tetrahydrothiophene, tetrahydrothiopyran, oxetane,tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine,for example cyclopropane, which carry any adjacent chain members of achain representing R²³ and/or the group R²⁴ and/or the ring comprisingthe groups Y and Z which is depicted in formula I, on two adjacent ringcarbon atoms or on the ring nitrogen atom and an adjacent ring carbonatom, and which rings can all be substituted as indicated.

In case a ring formed by two of the groups R²⁶ or one group R²⁵ and onegroup R²⁶, together with the comprised chain members, comprises morethan one chain members, besides being the group C(R²⁶)(R²⁶) thecomprised chain members can also be hetero chain members including thegroup N(R²⁵), which then are hetero ring members of the formed ring,wherein ar least one group C(R²⁶)(R²⁶) is present. In one embodiment ofthe invention, the total number of hetero ring members in such a ring iszero, one or two, in another embodiment zero or one, in anotherembodiment zero, in another embodiment one. In one embodiment of theinvention, hetero ring members in such a ring are chosen from the seriesconsisting of N, N(R³⁴), O and S, in another embodiment form the seriesconsisting of N, N(R³⁴) and O, in another embodiment from the seriesconsisting of N and N(R³⁴), in another embodiment from the seriesconsisting of N(R³⁴) and O, in another embodiment from the seriesconsisting of N(R³⁴), and in another embodiment hetero ring members insuch a ring are N, and in still another embodiment hetero ring membersin such a ring are O, wherein a hetero ring member N in a ring formed bytwo of the groups R²⁶ or one group R²⁵ and one group R²⁶, together withthe comprised chain members, is the nitrogen atom of a hetero chainmember N(R²⁵).

In one embodiment of the invention, the number of substituents which areoptionally present in a ring formed by two of the groups R²⁶ or onegroup R²⁵ and one group R²⁶, together with the comprised chain members,is 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in anotherembodiment 0, 1 or 2, in another embodiment 0 or 1, in anotherembodiment 0. In one embodiment of the invention, (C₁-C₄)-alkylsubstituents which are present in a ring formed by two of the groups R²⁶or one group R²⁵ and one group R²⁶, together with the comprised chainmembers, are methyl. In one embodiment of the invention substituentspresent in a ring formed by two of the groups R²⁶ or one group R²⁵ andone group R²⁶, together with the comprised chain members, are fluorine,in another embodiment they are identical or different (C₁-C₄)-alkylgroups, for example methyl.

Examples of specific groups R²³ including specific groups R²⁶ containedtherein are given in the following examples of groups of the formula II,which groups are bonded to the ring comprising the groups Y and Z whichis depicted in formula I by the free bond represented by the terminalhyphen or the terminal line in the structural formula, and from whichgroups of the formula II the groups R²³ themselves are obtained byremoving the group R²⁴, wherein in these groups of the formula II thegroup R²⁴ is defined as above or below:

In one embodiment of the invention, R²³ is chosen from a direct bond andany one or more of the chains R²³ in the preceding examples of groups ofthe formula II and, likewise, the group of the formula II is chosen fromthe group R²⁴ and any one or more of the preceding examples of thegroups of the formula II.

In one embodiment of the invention, R³² and R³⁴ are independently ofeach other chosen from the series consisting of hydrogen, R³⁵,R³⁵—C(O)—, R³⁵—O—C(O)— and phenyl, in another embodiment from the seriesconsisting of hydrogen, R³⁵, R³⁵—C(O)— and R³⁵—O—C(O)—, in anotherembodiment from the series consisting of hydrogen, R³⁵ and R³⁵—C(O)—, inanother embodiment from the series consisting of hydrogen, R³⁵ andphenyl, in another embodiment from the series consisting of hydrogen andR³⁵ In one embodiment of the invention, the groups R³⁵ occurring in R³²and R³⁴ are independently of each other chosen from (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in anotherembodiment from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂—, inanother embodiment from (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from (C₁-C₆)-alkyl, in another embodiment from (C₁-C₄)-alkyl,which are all optionally substituted by one or more identical ordifferent substituents R⁷⁰ and wherein in these groups besides anysubstituents R⁷⁰ one or more fluorine substituents are optionallypresent and in cycloalkyl groups one or more (C₁-C₄)-alkyl substituentsare optionally present as applies to alkyl and cycloalkyl groups ingeneral.

In one embodiment of the invention, the number of substituents R⁷⁰ whichare optionally present in a group R³⁵ occurring in R³² and R³⁴ besidesany fluorine substituents and, in the case of a cycloalkyl group, alkylsubstituents, is, independently of each other group, 0, 1, 2, 3 or 4, inanother embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, inanother embodiment 0 or 1, in another embodiment 0. In one embodiment ofthe invention, substituents R⁷⁰ which are optionally present in a groupR³⁵ occurring in R³² and R³⁴ are, independently of each other group,chosen from the series consisting of HO— and R⁷¹—O—.

In one embodiment of the invention, R⁵⁰ is chosen from R⁵¹—O— andR⁵²—NH—, in another embodiment from R⁵¹—O— and H₂N—. In anotherembodiment R⁵⁰ is R⁵¹—O—.

In one embodiment of the invention, R⁵¹ is hydrogen. In anotherembodiment of the invention, R⁵¹ is R⁵⁴.

In one embodiment of the invention, R⁵² is chosen from the seriesconsisting of hydrogen, R⁵⁵ and R⁵⁶—S(O)₂—, in another embodiment fromthe series consisting of hydrogen, (C₁-C₄)-alkyl which is optionallysubstituted by one or more identical or different substituents R⁷⁰, andR⁵⁶—S(O)₂—, in another embodiment from the series consisting ofhydrogen, unsubstituted (C₁-C₄)-alkyl and R⁵⁶—S(O)₂—, in anotherembodiment from the series consisting of hydrogen, unsubstituted methyland R⁵⁶—S(O)₂—, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl which is optionally substituted by one ormore identical or different substituents R⁷⁰, in another embodiment fromthe series consisting of hydrogen and unsubstituted (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen andunsubstituted methyl. In another embodiment of the invention, R⁵² ishydrogen.

In one embodiment of the invention, R⁵³ is chosen from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl which is optionally substitutedby one or more identical or different substituents R⁷⁰, in anotherembodiment from the series consisting of hydrogen and unsubstituted(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and unsubstituted methyl. In another embodiment of theinvention, R⁵³ is hydrogen. In one embodiment of the invention, R⁵¹, R⁵²and R⁵³ are independently of each other chosen from the seriesconsisting of hydrogen and unsubstituted (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen and unsubstituted(C₁-C₃)-alkyl, in another embodiment from the series consisting ofhydrogen and unsubstituted (C₁-C₂)-alkyl.

In one embodiment of the invention, R⁵⁴ is chosen from (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in anotherembodiment from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂—, inanother embodiment from (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from (C₁-C₆)-alkyl, in another embodiment from (C₁-C₄)-alkyl,in another embodiment from (C₁-C₃)-alkyl, which are all optionallysubstituted by one or more identical or different substituents R⁷⁰ andwherein in these groups besides any substituents R⁷⁰ one or morefluorine substituents are optionally present and in cycloalkyl groupsone or more (C₁-C₄)-alkyl substituents are optionally present as appliesto alkyl and cycloalkyl groups in general. In one embodiment of theinvention, the number of substituents R⁷⁰ which are optionally presentin a group R⁵⁴ besides any fluorine substituents and, in the case of acycloalkyl group, any alkyl substituents, is 0, 1 or 2, in anotherembodiment 0 or 1, in another embodiment 1, in another embodiment 0. Inanother embodiment of the invention, a group R⁵⁴ is neither substitutedby R⁷⁰ nor by fluorine substituents nor, in the case of a cycloalkylgroup, by alkyl substituents, and R⁵⁴ in this embodiment thus is chosen,for example, from the series consisting of C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂—, or fromthe series consisting of (C₁-C₆)-alkyl, or from the series consisting of(C₁-C₄)-alkyl, or from the series consisting of (C₁-C₃)-alkyl, which areall unsubstituted. In one embodiment of the invention, substituents R⁷⁰which are optionally present in a group R⁵⁴, are independently of eachother chosen from the series consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—,HO—C(O)— and R⁷¹—O—C(O)—, in another embodiment from the seriesconsisting of HO—, R⁷¹—O— and R⁷¹—C(O)—O—, in another embodiment fromthe series consisting of HO— and R⁷¹—C(O)—O—.

In one embodiment of the invention, R⁵⁶ is chosen from the seriesconsisting of phenyl which is optionally substituted as indicated aboveor below, and unsubstituted (C₁-C₄)-alkyl, in another embodiment fromthe series consisting of phenyl which is optionally substituted asindicated above or below, and unsubstituted methyl, in anotherembodiment from unsubstituted (C₁-C₄)-alkyl, in another embodiment fromunsubstituted (C₁-C₃)-alkyl. In another embodiment R⁵⁶ is unsubstitutedmethyl, in another embodiment phenyl which is optionally substituted asindicated.

In one embodiment of the invention, R⁶⁰ is chosen from the seriesconsisting of hydrogen and methyl. In another embodiment R⁶⁰ ishydrogen. In another embodiment R⁶⁰ is (C₁-C₄)-alkyl, for examplemethyl.

In one embodiment of the invention, a group R⁷⁰ in any of itsoccurrences is, independently of groups R⁷⁰ in other occurrences andunless specified otherwise, chosen from the series consisting of HO—,R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—,R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—, R⁷¹—S(O)₂—N(R⁷¹)—,HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—, R⁷¹—N(R⁷¹)—C(O)— andoxo, in another embodiment from the series consisting of HO—, R⁷¹—O—,R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—,R⁷¹—S(O)₂—NH—, HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R⁷¹)—C(O)— and oxo, in another embodiment from the seriesconsisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, HO—C(O)—,R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—, R⁷¹—N(R⁷¹)—C(O)— and oxo, inanother embodiment from the series consisting of HO—, R⁷¹—O—,R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—, R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—,R⁷¹—S(O)₂—NH— and oxo, in another embodiment from the series consistingof HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)— and oxo, in anotherembodiment from the series consisting of HO—, R⁷¹—O—, R⁷¹—S(O)_(m)— andoxo, in another embodiment from the series consisting of HO—, R⁷¹—O—,R⁷¹—C(O)—O— and R⁷¹—S(O)_(m)—, in another embodiment from the seriesconsisting of HO— and R⁷¹—O—, in another embodiment from the seriesconsisting of HO— and R⁷¹—C(O)—O—, in another embodiment from the seriesconsisting of HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R⁷¹)—C(O)—, in another embodiment from the series consisting ofHO—C(O)—, and R⁷¹—O—C(O)—, and in another embodiment R⁷⁰ is HO—, whereinR⁷¹ is defined as indicated above or below. In the latter embodiment, inwhich R⁷⁰ is HO—, a (C₁-C₆)-alkyl group, for example, which isoptionally substituted by the said R⁷⁰, can among others be a group suchas (C₁-C₆)-alkyl, HO—(C₁-C₆)-alkyl-, i.e. hydroxy-(C₁-C₆)-alkyl-, (HO)₂(C₂-C₆)-alkyl-, i.e. dihydroxy-(C₂-C₆)-alkyl-, and a (C₁-C₄)-alkyl groupwhich is optionally substituted by R⁷⁰, can among others be a group suchas (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, i.e. hydroxy-(C₁-C₄)-alkyl-, (HO)₂(C₂-C₄)-alkyl-, i.e. dihydroxy-(C₂-C₄)-alkyl-, wherein the alkyl groupsare optionally substituted by one or more fluorine substituents. In oneembodiment of the invention, a carbon atom does not carry more than oneHO— group.

In one embodiment of the invention, R⁷¹ is chosen from (C₁-C₄)-alkyl,cyclopropyl and cyclopropyl-CH₂—, in another embodiment from(C₁-C₄)-alkyl and cyclopropyl, in another embodiment from (C₁-C₄)-alkyl,in another embodiment from (C₁-C₃)-alkyl, unless specified otherwise.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, substituents andnumbers are defined as in any of the specified embodiments ordefinitions of the elements or have one or more of the specific meaningswhich are mentioned herein as examples of elements, wherein allcombinations of one or more specified embodiments and/or definitionsand/or specific meanings of the elements are a subject of the presentinvention. Also with respect to all such compounds of the formula I, alltheir stereoisomeric forms and mixtures of stereoisomeric forms in anyratios, and their physiologically acceptable salts are a subject of thepresent invention.

Likewise, also with respect to all specific compounds disclosed herein,such as the example compounds which represent embodiments of theinvention wherein the various groups and numbers in the generaldefinition of the compounds of the formula I have the specific meaningspresent in the respective specific compound, it applies that all theirstereoisomeric forms and mixtures of stereoisomeric forms in any ratio,and their physiologically acceptable salts are a subject of the presentinvention. A subject of the invention also are all specific compoundsdisclosed herein, irrespective thereof whether they are disclosed as afree compound and/or as a specific salt, both in the form of the freecompound and in the form of all its physiologically acceptable salts.Thus, a subject of the invention also is a compound of the formula Iwhich is chosen from any of the specific compounds of the formula Iwhich are disclosed herein, or is any one of the specific compounds ofthe formula I which are disclosed herein, irrespective thereof whetherthey are disclosed as a free compound and/or as a specific salt, or aphysiologically acceptable salt thereof, wherein the compound of theformula I is a subject of the invention in any of its stereoisomericforms or a mixture of stereoisomeric forms in any ratio whereapplicable.

As an example of compounds of the invention which with respect to anystructural elements are defined as in specified embodiments of theinvention or definitions of such elements, compounds of the formula Imay be mentioned wherein ring A is a 3-membered to 8-membered monocyclicring which comprises 0, 1 or 2 identical or different hetero ringmembers chosen from the series consisting of N, N(R⁰), O, S, S(O) andS(O)₂, and which is saturated or comprises 1 double bond, wherein ring Ais optionally substituted on ring carbon atoms by one or more identicalor different substituents chosen from the series consisting of halogen,R¹, R², (O₂—C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—,R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—,R¹—C(O)—NH—, R¹—C(O)—N(R¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R)—, R¹—C(O)—,HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—,H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, F₅S—, NC—, oxo and methylene;

-   Y is chosen from the series consisting of S, C(R¹²)═C(R¹³), and    C(R¹⁵)═N;-   Z is C(R¹⁶);-   R²⁰ is hydrogen;-   and all other groups and numbers are defined as in the general    definition of the compounds of the formula I or in any specified    embodiments of the invention or definitions of structural elements,    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and their physiologically acceptable salts.

As another such example compounds of the formula I may be mentioned,wherein ring A is a cyclohexane ring or cycloheptane ring which isoptionally substituted on ring carbon atoms by one or more identical ordifferent substituents chosen from the series consisting of halogen, R¹,R², (C₂-C₆)-alkenyl, HO—, R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, R¹—S(O)_(m)—, H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—,R—C(O)—N(R¹)—, R¹—S(O)₂—NH—, R¹—S(O)₂—N(R¹)—, R¹—C(O)—, HO—C(O)—,R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—, R¹—N(R¹)—C(O)—, H₂N—S(O)₂—,R¹—NH—S(O)₂—, R¹—N(R)—S(O)₂—, F₅S—, NC—, oxo and methylene;

-   Y is chosen from the series consisting of S, C(R¹²)═C(R¹³) and    C(R¹⁵)═N;-   Z is C(R¹⁶);-   R²⁰ is hydrogen;-   and all other groups and numbers are defined as in the general    definition of the compounds of the formula I or in any specified    embodiments of the invention or definitions of structural elements,    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and their physiologically acceptable salts.

As another such example compounds of the formula I may be mentioned,wherein R²¹ is chosen from the series consisting of hydrogen, halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-C(O)—, NC— and Het¹, or togetherwith R¹³ or R¹⁴ forms a chain as specified in the definition of R¹³ andR¹⁴;

-   R²² is a group of the formula II    R²⁴—R²³—  II-   R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain    members of which 0 or 1 chain members are hetero chain members    chosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂    and the other chain members are identical or different groups    C(R²⁶)(R²⁶);-   and all other groups and numbers are defined as in the general    definition of the compounds of the formula I or in any specified    embodiments of the invention or definitions of structural elements,    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and their physiologically acceptable salts.

As another such example compounds of the formula I may be mentioned,wherein ring A is a cyclohexane ring or a cycloheptane ring which isoptionally substituted by one or two identical or different substituentschosen from the series consisting of halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—;

-   Y is chosen from the series consisting of C(R¹²)═C(R¹³) and    C(R¹⁵)═N;-   Z is C(R¹⁶);-   R¹², R¹³, R¹⁵ and R¹⁶ are independently of each other chosen from    the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl; or R¹³    forms together with R²¹ a chain which is chosen from the series    consisting of —O—C(R¹⁸)(R¹⁸)—O—, —CH₂—CH₂—CH₂, —CH₂—O—CH₂—,    —CH₂—CH₂—CH₂—CH₂— and —O—C(R¹⁸)(R¹⁸)—C(R¹⁸)(R¹⁸)—O;-   R¹⁸ is chosen from the series consisting of hydrogen or fluorine;-   R²¹ is chosen from the series consisting of hydrogen, halogen,    (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,    (C₁-C₄)-alkyl-C(O)—, (C₁-C₄)-alkyl-O—(C₁-C₄)alkyl-,    HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, NC— and    oxetanyl, or together with R¹³ forms a chain as specified in the    definition of R¹³;-   R²² is a group of the formula II    R²⁴—R²³—  II-   R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain    members of which 0 or 1 chain members are hetero chain members    chosen from the series consisting of O and S, and the other chain    members are identical or different groups C(R²⁶)(R²⁶);-   R²⁴ is a benzene ring which is optionally substituted by one or more    identical or different substituents chosen from the series    consisting of halogen, R³³, oxetanyl, HO—, R³³—O—, R³³—S(O)_(m)—,    H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—S(O)₂—NH—, HO—C(O)—,    R³³—O—C(O)—, H₂N—C(O)—, R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—;-   R²⁶, independently of each other group R²⁶, is chosen from the    series consisting of hydrogen, fluorine, (C₁-C₄)-alkyl, or two of    the groups R²⁶ which are bonded to the same carbon atom in the    chain, together with the carbon atom carrying them, form a    cyclopropane ring or an oxetane ring;-   R³³, independently of each other group R³³, is chosen from the    series consisting of (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, which are all optionally    substituted by one or more identical or different substituents R⁷⁰;-   R⁵⁰ is chosen from the series consisting of R⁵¹O— and R⁵² (R⁵³)N—;-   R⁵¹, R⁵² and R⁵³ are independently of each other chosen from the    series consisting of hydrogen and (C₁-C₄)-alkyl;-   R⁷⁰ is chosen from the series consisting of HO— and R⁷¹—O—;-   R⁷¹ is (C₁-C₄)-alkyl;-   m, independently of each other number m, is an integer chosen from    the series consisting of 0 and 2;-   cycloalkyl, independently of each other group cycloalkyl, and    independently of any other substituents on cycloalkyl, is optionally    substituted by one or more identical or different substituents    chosen from fluorine and (C₁-C₄)-alkyl; alkyl, independently of each    other group alkyl, and independently of any other substituents on    alkyl, is optionally substituted by one or more fluorine    substituents;-   in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and their physiologically acceptable salts.

A subject of the present invention is a compound of the formula I, whichis

-   trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylic    acid,-   cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic    acid,-   trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic    acid,-   cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylic    acid,-   trans-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylic    acid,-   cis-1-[(3′-Chloro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic    acid,-   trans-1-[(3′-Chloro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic    acid,-   trans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic    acid,-   cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylic    acid,-   cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylic    acid,-   cis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic    acid,-   trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylic    acid,-   trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethyl-cyclohexanecarboxylic    acid,-   cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethyl-cyclohexanecarboxylic    acid,-   Trans-1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic    acid,-   Cis-1-[(3′-chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic    acid,-   Cis-1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-trifluoromethyl-cyclohexanecarboxylic    acid, or-   cis-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic    acid,-   in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and their physiologically acceptable salts.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I which are outlined belowand by which the compounds are obtainable. For example, the preparationof the compounds of the formula I can be carried out by reacting acompound of the formula III with a compound of the formula IV withformation of an amide bond.

The ring A and the groups Y, Z, R²⁰ to R²² and R⁵⁰ in the compounds ofthe formulae III and IV are defined as in the compounds of the formula Iand additionally functional groups can be present in protected form orin the form of a precursor group which is later converted into the finalgroup. As an example of a precursor group which can favorably beemployed in the reaction of the compounds of the formulae III and IV,the carbonitrile group NC— (cyano group) may by mentioned as a precursorof the group —C(O)—R⁵⁰. Thus, compounds of the formula I can also beprepared by reacting a compound of the formula V, which carries a NC—group in the position of the group —C(O)—R⁵⁰, with a compound of theformula IV to give a compound of the formula VI which likewise carries aNC— group in the position of the group —C(O)—R⁵⁰ in the compounds of theformula I, and then converting the NC— group into the desired group—C(O)—R⁵⁰, for example into a carboxylic acid group or a carboxamidegroup by the well-known techniques for hydrolyzing carbonitriles. Forexample, the NC— group can be converted into the group —C(O)—R⁵⁰ in atwo step, one pot procedure by initial alcoholysis of the nitrile to theimino ester in a alcohol like ethanol or methanol in the presence of anacid such as hydrogen chloride under anhydrous conditions, and theformed imino ester converted into a carboxylic acid ester, i.e. acompound of the formula I in which R⁵⁰ is R⁵¹O, by subsequent additionof water. The ring A and the groups Y, Z, R²⁰ to R²² in the compounds ofthe formulae V and VI are defined as in the compounds of the formula I,and additionally can functional groups be present in protected form orin the form of a precursor group.

The group G in the compounds of the formula IV can be HO— (hydroxy),i.e. the compound of the formula IV can thus be a carboxylic acid, oranother group which can be replaced by the group N(R²⁰) in the compoundof the formula III or V in a substitution reaction, for example anaryloxy group such as optionally substituted phenoxy or an alkyloxygroup such as a (C₁-C₄)-alkyl-O— group, for example a (C₁-C₃)-alkyl-O—group like methoxy or ethoxy, or halogen, for example chlorine orbromine, and the compound of the formula IV can thus be a reactive esterlike an aryl ester or alkyl ester, for example a methyl ester or ethylester, or an acid halide, for example an acid chloride or acid bromide,of the respective carboxylic acid. The compound of the formulae III andV and/or the compound of the formula IV can also be employed, and thecompounds of the formulae I and VI obtained, in the form of a salt, forexample an acid addition salt such as an hydrohalide, for example ahydrochloride, of the compound of the formulae III and V and/or analkaline metal salt, for example a sodium salt, of a compound of theformula IV in which G is HO—. Likewise, in all other reactions in thepreparation of the compounds of the formula I, including the preparationof starting compounds, compounds can also be employed and/or productsobtained in the form a salt.

In case a compound of the formula IV is employed in which G is HO—, thecarboxylic acid group HO—C(O)— is generally activated in situ by meansof a customary amide coupling reagent or converted into a reactivecarboxylic acid derivative which can be prepared in situ or isolated.For example, the compound of the formula IV in which G is HO— can beconverted into an acid halide, e.g. the compound of the formula IV inwhich G is Cl or Br, by treatment with thionyl chloride, phosphoruspentachloride, phosphorus tribromide or oxalyl chloride, or treated withan alkyl chloroformate like ethyl chloroformate or isobutylchloroformate to give a mixed anhydride. Customary coupling reagentswhich can be employed, are propanephosphonic anhydride,N,N′-carbonyldiazoles like N,N′-carbonyldiimidazole (CDI), carbodiimideslike 1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide(DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC), carbodiimides together with additives like1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT),uronium-based coupling reagents likeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) orO-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), and phosphonium-based coupling reagents like(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP).

The reaction conditions for the preparation of the compounds of theformulae I and VI from compounds of the formulae III and V and compoundsof the formula IV depend on the particulars of the specific case, forexample the meaning of the group G or the employed coupling reagent, andare well known to a skilled person in view of the general knowledge inthe art. For example, in case a compound of the formula IV in which G isalkyl-O—, like methoxy or ethoxy, is reacted with a compound of theformula III or V, generally the reaction is carried out in an inertsolvent, for example a hydrocarbon or chlorinated hydrocarbon likebenzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform ordichloroethane, an ether like tetrahydrofuran (THF), dioxane, dibutylether, diisopropyl ether or dimethoxyethane (DME), or a mixture ofsolvents, at elevated temperatures, for example at temperatures fromabout 40° C. to about 140° C., in particular at temperatures from about50° C. to about 120° C., for example at about the boiling temperature ofthe solvent. In case a compound of the formula IV in which G is halogen,like chlorine or bromine, is reacted with a compound of the formula IIIor V, generally the reaction is likewise carried out in an inertsolvent, for example a hydrocarbon or chlorinated hydrocarbon or etherlike the aforementioned ones, an ester like ethyl acetate or butylacetate, a nitrile like acetonitrile, or water, or a mixture of solventsincluding a mixture of water and an organic solvent which is miscible orimmiscible with water, at temperatures from about −10° C. to about 100°C., in particular at temperatures from about 0° C. to about 80° C., forexample at about room temperature. Favorably, the reaction of a compoundof the formula IV in which G is halogen with a compound of the formulaIII or V is carried out in the presence of a base such as a tertiaryamine, like triethylamine, ethyldiisopropylamine, N-methylmorpholine orpyridine, or an inorganic base such as an alkaline metal hydroxide,carbonate or hydrogencarbonate, like sodium hydroxide, potassiumhydroxide, sodium carbonate or sodium hydrogencarbonate.

In case a compound of the formula IV in which G is HO— is reacted with acompound of the formula III or V and the carboxylic acid group isactivated by means of an amide coupling reagent such as, for example, acarbodiimide or TOTU, the reaction is generally carried out underanhydrous conditions in an inert aprotic solvent, for example an etherlike THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) orN-methylpyrrolidone (NMP), at temperatures from about −10° C. to about40° C., in particular at temperatures from about 0° C. to about 30° C.in the presence of a base such as a tertiary amine, like triethylamine,ethyldiisopropylamine or N-methylmorpholine. In case the compound of theformula III or V is employed in the form of an acid addition salt in thereaction with the compound of the formula IV, usually a sufficientamount of a base is added in order to liberate the free compound of theformula III or V.

As indicated above, during the formation of the amide bond between thecompounds of the formulae III and V and compounds of the formula IVfunctional groups in the compounds of the formulae III, IV and V can bepresent in protected form or in the form of a precursor group. Dependingon the particulars of the specific case, it may be necessary oradvisable for avoiding an undesired course of the reaction or sidereactions to temporarily block any functional groups by protectivegroups and remove them later, or to let functional groups be present inthe form of a precursor group which is later converted into the desiredfinal group. This applies correspondingly to all reactions in the courseof the synthesis of the compounds of the formula I including thesynthesis of intermediates outlined below and the synthesis of startingcompounds and building blocks. Respective synthetic strategies arecommonly used in the art. Details about protective groups and theirintroduction and removal are found in P. G. M. Wuts and T. W. Greene,Greene's Protective Groups in Organic Synthesis, 4. ed. (2007), JohnWiley & Sons, for example. Examples of protective groups which may bementioned, are benzyl protective groups which may occur in the form ofbenzyl ethers of hydroxy groups and benzyl esters of carboxylic acidgroups from which the benzyl group can be removed by catalytichydrogenation in the presence of a palladium catalyst, tert-butylprotective groups which may occur in the form of tert-butyl esters ofcarboxylic acid groups from which the tert-butyl group can be removed bytreatment with trifluoroacetic acid, acyl protective groups which may beused to protect hydroxy groups and amino groups in the form of estersand amides and which can be cleaved by acidic or basic hydrolysis, andalkyloxycarbonyl protective groups which may occur in the form oftert-butoxycarbonyl derivatives of amino groups which can be cleaved bytreatment with trifluoroacetic acid. Undesired reactions of carboxylicacid groups, for example the carboxylic acid group present in thecompound of the formula III in case R⁵⁰ is HO—, can also be avoided byemploying them in the reaction of the compounds of the formulae III andIV in the form of other esters, for example in the form of alkyl esterslike the methyl or ethyl ester which can be cleaved by hydrolysis, forexample by means of an alkaline metal hydroxide like sodium hydroxide orlithium hydroxide. Another example of precursor groups besides cyanogroups (NC—, N≡C—), which were already mentioned, are nitro groups whichcan be converted into amino groups by catalytic hydrogenation or byreduction with sodium dithionite, for example. A further example of aprecursor group is an oxo group, which may initially be present in thecourse of the synthesis of compounds of the formula I containing ahydroxy group, and which can be reduced, for example with a complexhydride such as sodium borohydride, or reacted with an organometalliccompound, for example a Grignard compound. If any protective groups orprecursor groups are present in the compounds of the formulae III, IVand V and the direct product of the reaction of the compound of theformula III or V with the compound of the formula IV is not yet thedesired final compound, the removal of the protective group orconversion into the desired compound can in general also be carried outin situ.

The compounds of the formula IV are commercially available or can beobtained according to, or analogously to, procedures described in theliterature. Customarily, in synthetic procedures for the preparation ofcompounds of the formula IV compounds are prepared in which the group Gin the compounds of the formula IV is a group like (C₁-C₄)-alkyl-O— andthe group G-C(O)— thus is a (C₁-C₄)-alkyl ester group, or the groupG-C(O)— is any other ester group such as a benzyl esterphenyl-CH₂—O—C(O)— and the group G thus is a benzyloxy group. Compoundsof the formula IV in which G is HO—, can be obtained from such compoundsof the formula IV by acidic or basic hydrolysis of alkyl esters or byhydrogenation of benzyl esters under standard conditions. Compounds ofthe formula IV in which G is HO— can then be converted into compounds ofthe formula IV in which G is halogen as already explained above, whichlatter compounds can be converted into compounds in which G is aryloxy,for example by reaction with a hydroxyarene such as phenol. In thefollowing, various synthetic procedures for the preparation of compoundsof the formula IV in which the group R²³ in the group R²⁴—R²³—, i.e. inthe group of the formula II which represents one of the groups R²¹ andR²², has different meanings, are exemplarily outlined.

In a procedure for the preparation of compounds of the formula IV inwhich the group R²³ is a chain wherein the terminal chain member whichis bonded to the ring comprising the groups Y and Z, is a hetero chainmember, a compound of the formula VII is reacted with a compound of theformula VIII to give a compound of the formula IVa.

In the compounds of the formulae IVa, VII and VIII the groups Y, Z andR²⁴ are defined as in the compounds of the formula I. The group R⁸⁰ ischosen from the series consisting of hydrogen, halogen, R³⁰, HO—,R³⁰—O—, R³⁰—C(O)—O—, R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—,R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—, R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—,R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—, R³⁰—O—C(O)—, H₂N—C(O)—,R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—, R³⁰—NH—S(O)₂—,R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹; or together with R¹³ or R¹⁴ formsa chain as specified in the definition of R¹³ and R¹⁴; i.e. R⁸⁰ has themeaning of the one of the groups R²¹ and R²² in the compounds of theformula I which is not a group of the formula II. Additionally,functional groups in the compounds of the formulae IVa, VII and VIII canbe present in protected form or in the form of a precursor group whichis later converted into the final group. The group G¹-C(O)— is an estergroup and the group G¹ a group such as (C₁-C₄)-alkyl-O— or benzyloxy.The group X is a hetero chain member as specified in the definition ofR²³, i.e. a group chosen from the series consisting of N(R²⁵), O, S,S(O) and S(O)₂, in particular from the series consisting of N(R²⁵), Oand S. The groups R^(23a) and X together represent the group R²³ asspecified above wherein a terminal chain member which is a hetero chainmember, is bonded to the ring comprising the groups Y and Z. R^(23a)thus is a direct bond or a chain consisting of 1 to 4 chain members ofwhich 0 or 1 chain member is a hetero chain member chosen from theseries consisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that theterminal chain member adjacent to the group L² can only be a heterochain member which leads to the formation of compound of the formula IVain which one of the group X and the said terminal chain member is chosenfrom the series consisting of S(O) and S(O)₂ and the other is chosenfrom the series consisting of N(R²⁵), O and S, and the other chainmembers are identical or different groups C(R²⁶)(R²⁶). As is symbolizedby the bonds connecting the groups R⁸⁰ and XH in the compounds of theformula VII, as well as the groups R⁸⁰ and X—R^(23a)—R²⁴ in thecompounds of the formula IVa, which bonds are not directed to a specificring carbon atom, each of the said two groups can be located in each ofthe two positions of the moiety C═C in the ring comprising the groups Yand Z which is depicted in the formulae. I.e., R⁸⁰ can be located on thering carbon which is adjacent to the group Y and the other of the twogroups on the ring carbon atom which is adjacent to the group Z, as wellas R⁸⁰ can be located on the ring carbon which is adjacent to the groupZ and the other of the two groups on the ring carbon atom which isadjacent to the group Y. This applies to all compounds defined belowcontaining a group R⁸⁰ and a second group in which the bonds connectingthe group to the ring comprising the groups Y and Z are not directed toa specific ring carbon atoms. The group L² in the compounds of theformula VIII is a leaving group which can be replaced with the group X,such as halogen, fore example chlorine or bromine, a sulfonyloxy group,for example methanesulfonyloxy, trifluoromethanesulfonyloxy ortoluene-4-sulfonyloxy, or hydroxy, for example.

The reaction of a compound of the formula VII with a compound of theformula VIII is a nucleophilic substitution reaction which can becarried out under standard conditions for such reactions which are wellknown to a person skilled in the art. Generally, the reaction isperformed in an inert solvent, for example a hydrocarbon or chlorinatedhydrocarbon like benzene, toluene, xylene, chlorobenzene,dichloromethane, chloroform or dichloroethane, an ether like THF,dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol likemethanol, ethanol or isopropanol, a ketone like acetone or butan-2-one,an ester like ethyl acetate or butyl acetate, a nitrile likeacetonitrile, an amide like DMF or NMP, a sulfoxide like DMSO or asulfone like sulfolane, or a mixture of solvents, at temperatures fromabout −10° C. to about 120° C., in particular at temperatures from about0° C. to about 100° C., depending on the particulars of the specificcase. In many cases it is favorable for enhancing the nucleophilicity ofthe compound of the formula VII and/or binding an acid which isliberated during the reaction, to add a base, for example a tertiaryamine, such as triethylamine, ethyldiisopropylamine orN-methylmorpholine, or an inorganic base such as an alkaline metalhydride, hydroxide, carbonate or hydrogencarbonate like sodium hydride,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, cesium carbonate or sodium hydrogencarbonate, or an alkoxideor amide such as sodium methoxide, sodium ethoxide, potassium methoxide,potassium tert-butoxide, sodium amide or lithium diisopropylamide. Acompound of the formula VII can also be treated with a base andconverted into a salt in a separate step. Compounds of the formula VIIIin which the group L² is hydroxy can favorably be reacted with compoundsof the formula VII under the conditions of the Mitsunobu reaction in thepresence of an azodicarboxylate like diethyl azodicarboxylate ordiisopropyl azodicarboxylate and a phosphine like triphenylphosphine ortributylphosphine in an inert aprotic solvent such as an ether like THFor dioxane (cf. O. Mitsunobu, Synthesis (1981), 1-28).

In another procedure, compounds of the formula IVa can be obtained byreacting a compound of the formula IX with a compound of the formula X.

In the compounds of the formulae IX and X the groups Y, Z and R²⁴ aredefined as in the compounds of the formula I. The group R⁸⁰ is definedas in the compounds of the formulae IVa and VII, i.e. it has the meaningof the one of the groups R²¹ and R²² in the compounds of the formula Iwhich is not a group of the formula II. Additionally, functional groupsin the compounds of the formulae IX and X can be present in protectedform or in the form of a precursor group which is later converted intothe final group. The group G¹-C(O)— is an ester group and the group G¹ agroup such as (C₁-C₄)-alkyl-O— or benzyloxy. The group X is a heterochain member as specified in the definition of R²³, i.e. a group chosenfrom the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, inparticular from the series consisting of N(R²⁵), O and S. In thecompound of the formula X the groups R^(23a) and X together representthe group R²³ as specified above wherein a terminal chain member whichis a hetero chain member, is bonded to the ring comprising the groups Yand Z in the obtained compounds of the formula IVa. R^(23a) thus is adirect bond or a chain consisting of 1 to 4 chain members of which 0 or1 chain member is a hetero chain member chosen from the seriesconsisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that the terminalchain member adjacent to the group X can only be a hetero chain memberif one of the group X and the said terminal chain member is chosen fromthe series consisting of S(O) and S(O)₂ and the other is chosen from theseries consisting of N(R²⁵), O and S, and the other chain members areidentical or different groups C(R²⁶)(R²⁶). The group L³ in the compoundsof the formulae IX is a leaving group which can be replaced with thegroup X, such as halogen like fluorine, chlorine, bromine or iodine, ora sulfonyloxy group like methanesulfonyloxy ortrifluoromethanesulfonyloxy, for example. The reaction of a compound ofthe formula IX with a compound of the formula X formally is anucleophilic substitution reaction at the ring comprising the groups Yand Z which can in particular be performed in case of compounds of theformulae IX which are susceptible to such a reaction because of thepresence of electron-withdrawing substituents or ring hetero atoms. Thereaction can be carried out under standard conditions for such reactionswhich are well known to a person skilled in the art. The explanations onthe reaction conditions such as solvents or bases which are favorablyadded, which are given above with respect to the reaction of a compoundof the formula VII with a compound of the formula VIII applycorrespondingly to the reaction of a compound of the formula IX with acompound of the formula X.

The explanations on the reaction of a compound of the formula VII with acompound of the formula VIII also apply correspondingly to reactions forthe preparation of compounds of the formula I in which a hetero chainmember in the group R²³ is not present in the terminal position of thechain which is adjacent to the ring comprising the groups Y and Z, butis separated from the said ring by one or more groups C(R²⁶)(R²⁶), whichreactions are of the same type as the reactions outlined above. As anexample, the preparation of a compound of the formula IVb from acompound of the formula XI and a compound of the formula XII may beillustrated.

In the compounds of the formulae IVb, XI and XII the groups Y, Z and R²⁴are defined as in the compounds of the formula I. The group R⁸⁰ isdefined as in the compounds of the formulae IVa and VII, i.e. it has themeaning of the one of the groups R²¹ and R²² in the compounds of theformula I which is not a group of the formula II. Additionally,functional groups in the compounds of the formulae IX and X can bepresent in protected form or in the form of a precursor group which islater converted into the final group. Additionally, functional groups inthe compounds of the formulae IVb, XI and XII can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group G¹-C(O)— is an ester group andthe group G¹ a group such as (C₁-C₄)-alkyl-O— or benzyloxy. The group Xis a hetero chain member as specified in the definition of R²³, i.e. agroup chosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂,in particular from the series consisting of N(R²⁵), O and S. The groupsR^(23b), R^(23c) and X in the compounds of the formulae IVb togetherrepresent the group R²³ as specified above wherein X is a said heterochain member. In case R²³ comprises only one hetero chain member, thegroup R^(23b) in the compounds of the formulae IVb and XI is a chainconsisting of 1 to 4 identical or different groups C(R²⁶)(R²⁶) and thegroup R^(23c) in the compounds of the formulae IVb and XII is a directbond or a chain consisting of 1 to 3 identical or different groupsC(R²⁶)(R²⁶), provided that the total number of groups C(R²⁶)(R²⁶) is notgreater than 4. In the group R^(23c) in the compounds of the formulaeIVb and XII a further hetero chain member chosen from the seriesconsisting of N(R²⁵), O, S, S(O) and S(O)₂ can be present instead of oneof the groups C(R²⁶)(R²⁶), provided that such further hetero chainmember can only be present in the terminal position adjacent to thegroup L² if one of the group X and the said chain member in the terminalposition is chosen from the series consisting of S(O) and S(O)₂ and theother is chosen from the series consisting of N(R²⁵), O and S. Theleaving group L² in the compounds of the formula XII is defined as inthe compounds of the formula VIII. Correspondingly as outlined abovewith respect to the synthesis of the compounds of the formula IVa, whichcan be prepared by reacting a compound of the formula VII with acompound of the formula VIII as well as by reacting a compound of theformula IX with a compound of the formula X, compounds of the formulaIVb can also be prepared by reacting a compound which is defined as thecompound of the formula XI but contains a group L² instead of the groupXH, with a compound which is defined as the compound of the formula XIIbut contains a group XH instead of the group L².

In a procedure for the preparation of compounds of the formula IV inwhich the group R²³ is a chain which does not comprise any hetero chainmember, a carbonyl compound of the formula XIII is condensed with acompound of the formula XIV to give an olefin of the formula IVc whichcan subsequently be hydrogenated to give a compound of the formula IVd,respectively, or reacted with an organometallic compound of the formulaXV to give an alcohol of the formula IVe which likewise can subsequentlybe hydrogenated to give a compound of the formula IVf.

In the compounds of the formulae IVc to IVf, XIII, XIV and XV the groupsY, Z and R²⁴ are defined as in the compounds of the formula I. The groupR⁸⁰ is defined as in the compounds of the formulae IVa and VII, i.e. ithas the meaning of the one of the groups R²¹ and R²² in the compounds ofthe formula I which is not a group of the formula II. Additionally,functional groups in the compounds of the formulae IVc to IVf, XIII, XIVand XV can be present in protected form or in the form of a precursorgroup which is later converted into the final group. The group G¹-C(O)—is an ester group and the group G¹ a group such as (C₁-C₄)-alkyl-O— orbenzyloxy. The groups R^(a) and R^(b) are independently of each otherchosen from hydrogen and (C₁-C₄)-alkyl. The group R^(23d) is a directbond or a chain consisting of 1 to 3 identical or different groupsC(R²⁶)(R²⁶), the group R^(23e) a direct bond or a chain consisting of 1to 4 identical or different groups C(R²⁶)(R²⁶). The group L⁴ in thecompounds of the formula XIV is group which allows for the formation ofa double bond between the carbon atom carrying the group L⁴ and thecarbon atom of the aldehyde group or ketone group carrying the groupR^(a) in the compound of the formula XIII in a condensation reaction.Examples of suitable condensation reactions are the Wittig reaction andthe Wittig-Horner reaction, and examples of suitable groups L⁴ thus aretrisubstituted phosphonio groups, such as the triphenylphosphonio group,having an anion, such as a halide anion, as counterion, anddi((C₁-C₄)-alkyl)phosphonyl groups, such as the diethylphosphonyl group.The group L⁵ in the compounds of the formula XV is a metal such aslithium or a magnesium halide group like MgCl, MgBr or Mgl, and thecompound of the formula XV thus an organolithium compound or a Grignardcompound. The Wittig reaction and Wittig-Horner reaction and theaddition of the organometallic compound of the formula XV to thecompound of the formula XIII can be performed under standard conditionsin an inert solvent such as a hydrocarbon like benzene or toluene or anether like diethyl ether, THF, dioxane or DME. The Wittig reaction andthe Wittig-Horner reaction are performed in the presence of a base suchas a hydride like sodium hydride, an amide like sodium amide or lithiumdiisopropylamide, or an alkoxide like potassium tert-butoxide. Dependingon the particular case, instead of employing a phosphonium salt anddeprotonating it, also stable phosphorus ylides can directly be employedin the reaction. The hydrogenation of the double bond in the compoundsof the formula IVc to give the compounds of the formulae IVd, or of thebenzylic hydroxy group in the compounds of the formulae IVe to give thecompounds of the formulae IVf, can be performed in the presence of ahydrogenation catalyst such as palladium on charcoal.

Depending on the particulars of the specific case, various otherreactions can be used for preparing compounds of the formula IV. As anexample of the preparation of compounds in which the group R²³ is achain comprising three groups C(R²⁶)(R²⁶) and no hetero chain members,an aldol-type reaction of a compound of the formula XIIIa, which is acompound of the formula XIII in which the group R^(a) is methyl, with analdehyde of the formula XVI may be mentioned which leads to a compoundof the formula IVg or the formula IVm which can be reduced to a compoundof the formula IVh, IVk or IVn, for example.

In the compounds of the formulae IVg to IVn and XIIIa the groups Y and Zare defined as in the compounds of the formula I. The group R^(24a) inthe compounds of the formulae IVg to IVn and XVI is a group R³¹ or a3-membered to 10-membered ring as it can represent the group R²⁴ in thecompounds of the formula I which is bonded via a ring carbon atom, inparticular an aromatic ring such as an optionally substituted phenyl,naphthyl or heteroaryl group. The group R⁸⁰ is defined as in thecompounds of the formulae IVa and VII, i.e. it has the meaning of theone of the groups R²¹ and R²² in the compounds of the formula I which isnot a group of the formula II. Additionally, functional groups in thecompounds of the formulae IVg to IVn, XIIIa and XVI can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group G¹-C(O)— is an ester group andthe group G¹ a group such as (C₁-C₄)-alkyl-O— or benzyloxy.

The reaction of a compound of the formula XIIIa with a compound of theformula XIV to give an aldol addition product of the formula IVm or acondensation product of the formula IVg can be carried under standardconditions for the aldol reaction in the presence of a base, such as analkaline metal hydroxide like sodium hydroxide or potassium hydroxide,an alkoxide like sodium methoxide or sodium ethoxide or an amide likelithium diisopropylamide, in a solvent such as an alcohol like methanolor ethanol or an ether like diethyl ether, THF or dioxane. At lowertemperatures, for example at temperatures from about −80° C. to about−30° C., the compound of the formula IVm can be obtained, at highertemperatures, for example at temperatures from about 10° C. to about 60°C., or by treatment of the compound of the formula IVm with an acid, thecompound of the formula IVg can be obtained. The ketone function in thecompounds of the formulae IVg and IVm can be reduced to an alcoholfunction, for example with a complex hydride such as a borohydride likelithium borohydride or sodium borohydride, to give a compound of theformula IVh or IVn, respectively, which can be converted into a compoundof the formula IVk by dehydration in the presence of an acid and/orhydrogenation in the presence of a catalyst such as palladium oncharcoal, for example.

As a further example of reactions which can be used for preparingcompounds of the formula IV, transition metal-catalyzed C—C couplingreactions may be mentioned by which compounds can be obtained whereinthe group R²³ is a direct bond. Such compounds can be obtained from acompound of the formula IX and a boronic acid, for example an optionallysubstituted phenylboronic acid, cycloalkylboronic acid orheteroarylboronic acid. As catalyst in such reactions, a palladiumcompound such as bis(triphenylphosphine)palladium(II) chloride ortetrakis(triphenylphosphine)palla-dium(0) and a copper compound such ascopper(I) iodide can be used. Further details on such reactions arefound in N. Miyaura et al., Chem. Rev. 95 (1995), 2457-2483; and R.Chinchilla et al., Chem. Rev. 107 (2007), 874-922, for example.

The order in which groups are introduced in the course of the synthesisof a compound of the formula I, can also be different from the onesoutlined above. For example, instead of first preparing a compound ofthe formula IVa from a compound of the formula VII and a compound of theformula VIII, or from a compound of the formula IX and a compound of theformula X, and then reacting the compound of the formula IVa with acompound of the formula III to give a compound of the formula I, acompound of the formula III can also be reacted with a compound of theformula VII or a compound of the formula IX and the obtained compound ofthe formula XVII or XVIII reacted with a compound of the formula VIII orX, respectively, to give a compound of the formula Ik. This reactionsequence can also be performed with compounds of the formula V insteadof with compounds of the formula III, and in the obtained compounds thenitrile group converted into the group —C(O)—R⁵ to give compounds of theformula Ik.

In the compounds of the formulae Ik, XVII and XVIII the ring A and thegroups Y, Z, R²⁰, R²⁴ and R⁵⁰ are defined as in the compounds of theformula I. The groups X, R^(23a) and R⁸⁰ are defined as in the compoundsof the formula IVa. Thus, R⁸⁰ has the meaning of the one of the groupsR²¹ and R²² in the compounds of the formula I which is not a group ofthe formula II. The group X is a hetero chain member as specified in thedefinition of R²³, i.e. a group chosen from the series consisting ofN(R²⁵), O, S, S(O) and S(O)₂, in particular from the series consistingof N(R²⁵), O and S. The groups R^(23a) and X together represent thegroup R²³ as specified above wherein a terminal chain member which is ahetero chain member, is bonded to the ring comprising the groups Y andZ. R^(23a) thus is a direct bond or a chain consisting of 1 to 4 chainmembers of which 0 or 1 chain member is a hetero chain member chosenfrom the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, providedthat the terminal chain member adjacent to the group X can only be ahetero chain member if one of the group X and the said terminal chainmember is chosen from the series consisting of S(O) and S(O)₂ and theother is chosen from the series consisting of N(R²⁵), O and S, and theother chain members are identical or different groups C(R²⁶)(R²⁶).Additionally, functional groups in the compounds of the formulae Ik,XVII and XVIII can be present in protected form or in the form of aprecursor group which is later converted into the final group. Asindicated above and as applies to all compounds which contain a groupR⁸⁰ and another group which are connected to the ring comprising thegroups Y and Z by bonds which are not directed to a specific ring carbonatom, the groups R⁸⁰ and X in the compounds of the formula XVII, thegroups R⁸⁰ and L³ in the compounds of the formula XVIII, and the groupsR⁸⁰ and X—R^(23a)—R²⁴ in the compounds of the formula Ik can be locatedin each of the two positions of the moiety C═C in the ring comprisingthe groups Y and Z. The explanations given above with respect to thereaction of a compound of the formula III with a compound of the formulaIV, the reaction of a compound of the formula VII with a compound of theformula VIII, and the reaction of a compound of the formula IX with acompound of the formula X apply correspondingly to the reaction of acompound of the formula III with a compound of the formula VII or acompound of the formula IX, the reaction of a compound of the formulaXVII with a compound of the formula VIII, and the reaction of a compoundof the formula XVIII with a compound of the formula X. The order inwhich groups are introduced in the course of the synthesis of a compoundof the formula I, can also be varied with respect to other reactions.For example, a compound of the formula XVIII can be employed in atransition-metal catalyzed C—C coupling reaction as referred to above,or a compound of the formula XIIIa can be reacted with a compound of theformula III and the obtained compound modified at the CH₃—C(O)— group togive a compound of the formula I.

Like the compounds of the formula IV, the compounds of the formulae IIIand V are commercially available or can be obtained according to, oranalogously to, procedures described in the literature, for exampleaccording to the Bucherer-Bergs hydantoin procedure or the Streckerprocedure for the preparation of amino acids and amino acid nitriles,respectively. The following scheme illustrates the Bucherer-Bergshydantoin procedure for the synthesis of amino acids.

In the Bucherer-Bergs procedure, a ketone of the formula XIX isconverted into a hydantoin of the formula XX by reaction with a cyanidesource, such as an alkaline metal cyanide like sodium cyanide (NaCN),and ammonium carbonate ((NH₄)₂CO₃) in an inert solvent like a mixture ofan alcohol such as a (C₁-C₃)-alkanol and water, for example a mixture ofethanol and water, at temperatures from about 0° C. to about 150° C., inparticular at temperatures from about 20° C. to about 120° C., forexample at the reflux temperature of the employed solvent. The obtainedhydantoin can be converted into the respective amino acid of the formulaIIIa by hydrolysis, for example by hydrolysis with an aqueous acid likesulfuric acid or hydrochloric acid or by hydrolysis with an aqueousbases like sodium hydroxide or potassium hydroxide, at elevatedtemperatures, for example at the reflux temperature of the reactionmixture. For the reaction with the compound of the formula IV, the aminoacid of the formula IIIa can be protected by conversion into an aminoacid ester of the formula IIIb in which R⁹⁰ is a group such as(C₁-C₄)-alkyl, for example methyl or ethyl, or benzyl, by standardmethods which are well known to a person skilled in the art, for exampleby esterification with an alcohol like methanol or ethanol in thepresence of an acid like hydrogen chloride. The group A in the compoundsof the formulae XIX, XX, IIIa and IIIb is defined as in the compounds ofthe formula I and additionally functional groups can be present inprotected form or in the form of a precursor group which is laterconverted into the final group.

The following scheme illustrates the Strecker procedure for thesynthesis of amino acid nitriles.

In the Strecker procedure, a ketone of the formula XIX is converted intothe corresponding amino acid nitrile of the formula V by reaction with acyanide source, such as an alkaline metal cyanide like potassium cyanide(KCN), and a salt of an amine of the formula R²⁰—NH₂, wherein R²⁰ isdefined as in the compounds of the formula I, for example ammoniumchloride (NH₄Cl) in case R²⁰ is hydrogen or methylammonium chloride(CH₃—NH₃Cl) in case R²⁰ is methyl, in an inert solvent like water or analcohol such as a (C₁-C₃)-alkanol like methanol or ethanol or a mixturethereof with water, for example a mixture of ethanol and water, attemperatures from about 0° C. to about 150° C., in particular attemperatures from about 20° C. to about 120° C. or at temperatures fromroom temperature to the reflux temperature of the employed solvent. Theobtained amino acid nitrile of the formula V can be hydrolyzed to theamino acid of the formula IIIc, for example by hydrolysis with anaqueous acid like sulfuric acid or hydrochloric acid, or by hydrolysiswith an aqueous base like sodium hydroxide or potassium hydroxide, atelevated temperature, for example at temperatures from about 50° C. toabout 150° C., for example at the reflux temperature of the reactionmixture, and the amino acid then esterified to give a compound of theformula IIId, for use in the reaction with the compound of the formulaIV, as mentioned above with respect to the amino acids of the formulaIIIa. Alternatively, the amino acid nitrile of the formula V candirectly be reacted with a compound of the formula IV and the nitrilegroup hydrolyzed subsequently, as outlined above. The groups A and R²⁰in the compounds of the formulae IIIc and IIId and in the amines of theformula R²⁰—NH₂ are defined as in the compounds of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which is later converted into the finalgroup. The group R⁹⁰ in the compounds of the formula IIId is defined asin the compounds of the formula IIIb.

The Bucherer-Bergs procedure and the Strecker procedure were found togive different results with respect to the stereochemistry in case theprepared amino acid or amino acid nitriles contain additionalsubstituents in the ring A. It was described in the literature (cf. L.Munday, J. Chem. Soc. (1961), 4372-79) that, if the ring A is asubstituted cyclohexane ring, the Bucherer-Bergs procedure deliversproducts in which the substituent is in cis position with respect to theamino group in the obtained amino acid in case the substituent is in2-position or 4-position of the ring, but products in which thesubstituent is in trans position with respect to the amino group in casethe substituent is in the 3-position of the ring, whereas the Streckerprocedure delivers products in which the substituent is in transposition with respect to the amino group in case the substituent is in2-position or 4-position, but products in which the substituent is incis position with respect to the amino group in case the substituent isin the 3-position.

The cyclic ketones of the formula XIX which are employed in theBucherer-Bergs procedure and the Strecker procedure, are commerciallyavailable or can be synthesized by a broad variety of synthetic methodswhich are well known to a person skilled in the art. For example, acyclic ketone of the formula XIX can be synthesized by ring expansion ofthe respective ketone of smaller ring size of the formula XXI, whichcontains one ring carbon less, with diazomethane (CH₂N2), for exampleaccording to the procedure described in F. Alonso et al., Tetrahedron 51(1995), 10259-10280.

The ring expansion reaction with diazomethane is generally carried outin an inert solvent, for example an ether like diethyl ether,tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether ordimethoxyethane (DME), ethanol, methanol, a hydrocarbon,dichloromethane, chloroform or dichloroethane, or a mixture of solvents,at temperatures from about −78° C. to 50° C., in particular attemperatures from about −40° C. to about room temperature, for exampleat about 0° C. Diazomethane can be used as solution in an inert solvent,for example diethyl ether or THF, or can be generated in situ from anappropriate source for diazomethane likeN-methyl-N-nitroso-p-toluenesulfonamide (Diazald®) orN-methyl-N-nitrosourea. For example,N-methyl-N-nitroso-p-toluenesulfonamide can be added to a solution ofthe ketone in an inert solvent like a mixture of ethanol, methanol andwater containing a base like potassium hydroxide to generatediazomethane in situ. Alternatively, trimethylsilyl diazomethane can beadded to a solution of the ketone and an acid or silyl scavanger likeboron trifluoride etherate in an inert solvent like dichloromethane togenerate a diazomethane equivalent and to perform the ring enlargementreaction. As applies in general and is well known to a person skilled inthe art, the reaction conditions for ring enlargement of a ketone dependon the particulars of the specific case, for example on the substituentson the ring A.

An alternative synthetic approach to amino acid derivatives of theformulae IIIa and IIIb starts from malonic acid derivatives of theformula XXIII which can be dialkylated with a divalent alkylatingcompound of the formula XXII to give a cyclic dicarboxylic acidderivative of the formula XXIV analogously as described in V. Prelog etal., Helv. Chim. Acta 65 (1982), 2622-2644, and illustrated in thefollowing scheme.

The moiety A′ in the divalent alkylating compound of the formula XXIIcorresponds to the ring A in the compounds of the formula I except thatit does not contain the ring carbon atom present in A which carries thegroups N(R²⁰) and C(O)—R⁵⁰, and is defined accordingly, and the groupsL¹¹ and L¹² are leaving groups such as halogen, for example chlorine orbromine, or sulfonyloxy groups, for example methanesulfonyloxy ortrifluoromethanesulfonyloxy. The groups PG¹ and PG² in the malonic acidderivative of the formula XXIII and the compounds of the formulae XXIV,XXV, XXVI and XXVII have the function of protective groups of thecarboxylic acid groups and can be identical or different groups such as(C₁-C₄)-alkyl, for example methyl, ethyl or tert-butyl, or benzyl. Thealkylation reaction of the compounds of the formulae XXII and XXXIII isgenerally carried out in the presence of a base, for example an alkalinemetal hydride such as sodium hydride or an alkaline metal alkoxide suchas potassium tert-butoxide, in an inert solvent such as an ether likeTHF or diethyl ether or an amide like DMF or NMP or a nitrile likeacetonitrile at temperatures from about 0° C. to about 100° C.,depending on the particulars of the specific case. Subsequent to thealkylation reaction, one of the protective groups, for example PG², iscleaved, for example by treatment with an aqueous base like sodiumhydroxide or potassium hydroxide in the case of methyl or ethyl group.In the obtained compound of the formula XXV can the free carboxylic acidgroup be degraded to an amino group by degradation reactions which arewell known to a person skilled in the art. For example, the carboxylicacid can be activated by formation of a mixed anhydride, for example byreaction with a chloroformic acid ester like isobutyl chloroformate inthe presence of a base like triethylamine or N-methylmorpholine in aninert solvent like acetone, the mixed anhydride reacted in situ with analkaline metal azide like sodium azide to give the acid azide of theformula XXVI, which is subsequently heated in an inert solvent, forexample a hydrocarbon like toluene or xylene, to give the degradedisocyanate which can be hydrolyzed, for example with aqueous acid likehydrochloric acid to give the amino acid derivative of the formula XXVIIwhich already constitutes a compound of the formula IIIb or in which theprotective group PG¹ can be cleaved to give a compound of the formulaIIIa which can in turn be esterified as mentioned above to give acompound of the formula IIIb. Alternatively, the free carboxylic acidgroup in the compound of the formula XXV can be reacted with an azidetransfer reagent like diphenylphosphoryl azide to yield the acid azideof the formula XXVI which can be degraded as indicated. Further detailson the degradation procedures and the hydrolysis of the intermediaryisocyanate can be found in T. N. Wheeler, Synth. Commun. 18 (1988),141-149, and M. Oba et al., Tetrahedron 61 (2005), 593-598, for example.The group A in the compounds of the formulae XXIV, XXV, XXVI and XXVIIis defined as in the compounds of the formula I and additionally canfunctional groups be present in protected form or in the form of aprecursor group which is later converted into the final group.

The starting compounds and building blocks for the synthesis of thecompounds of the formula I can generally be prepared according toprocedures described in the literature or analogously to suchprocedures, or are commercially available. Exemplarily the preparationof compounds of the formula VIII in which R²⁴ is an optionallysubstituted phenyl or naphthyl group, R^(23a) is an optionallyalkyl-substituted CH₂CH₂ group and L² is a hydroxy group, may bementioned in which use can be made of the procedure for the coupling ofaryl halides with ester enolates described by M. Jørgensen et al., J.Am. Chem. Soc. 124 (2002), 12557-12565. In the said procedure anoptionally alkyl-substituted acetic acid ester, for example acetic acidtert-butyl ester or isobutyric acid methyl ester, is deprotonated with abase such as lithium dicyclohexylamide and reacted with an optionallysubstituted aryl bromide in the presence of a palladium compound such asbis(dibenzylideneacetone)palladium ortris(dibenzylideneactone)dipalladium and tri(tert-butyl)phosphine togive a 2-(optionally substituted aryl)acetic acid ester which isoptionally alkyl-substituted in the 2-position of the acetic acidmoiety. Reduction of the ester function under standard conditions, forexample with lithium aluminium hydride, then affords the 2-(optionallysubstituted aryl)ethanol which is optionally alkyl-substituted in the2-position.

For obtaining further compounds of the formula I, varioustransformations of functional groups can be carried out under standardconditions in compounds of the formula I or intermediates or startingcompounds in the synthesis of the compounds of the formula I. Forexample, a hydroxy group can be esterified to give a carboxylic acidester or a sulfonic acid ester, or etherified. Etherifications ofhydroxy groups can favorably be performed by alkylation with therespective halogen compound, for example a bromide or iodide, in thepresence of a base such an alkali metal carbonate like potassiumcarbonate or cesium carbonate in an inert solvent such as an amide likeDMF or NMP or a ketone like acetone or butan-2-one, or with therespective alcohol under the conditions of the Mitsunobu reactionreferred to above. A hydroxy group can be converted into a halide bytreatment with a halogenating agent. A halogen atom can be replaced witha variety of groups in a substitution reaction which may also be atransition-metal catalyzed reaction. A nitro group can be reduced to anamino group, for example by catalytic hydrogenation. An amino group canbe modified under standard conditions for alkylation, for example byreaction with a halogen compound or by reductive amination of a carbonylcompound, or for acylation or sulfonylation, for example by reactionwith an activated carboxylic acid or a carboxylic acid derivate like anacid chloride or anhydride or a sulfonic acid chloride. A carboxylicester group can be hydrolyzed under acidic or basic conditions to give acarboxylic acid. A carboxylic acid group can be activated or convertedinto a reactive derivative as outlined above with respect to thecompounds of the formula IX and reacted with an alcohol or an amine orammonia to give an ester or amide. A primary amide can be dehydrated togive a nitrile. A sulfur atom in an alkyl-S— group or in a heterocyclicring or a sulfur atom occurring in a chain representing the group R²³can be oxidized with a peroxide like hydrogen peroxide or a peracid togive a sulfoxide moiety S(O) or a sulfone moiety S(O)₂. A carboxylicacid group, carboxylic acid ester group and a ketone group can bereduced to an alcohol, for example with a complex hydride such allithium aluminium hydride, lithium borohydride or sodium borohydride.All reactions in the preparation of the compounds of the formula I areknown per se and can be carried out in a manner familiar to a personskilled in the art according to, or analogously, to procedures which aredescribed in the standard literature, for example in Houben-Weyl,Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley &Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2. ed. (1999), John Wiley & Sons, and thereferences quoted therein. Furthermore, besides by techniques ofsolution chemistry, the compounds of the formula I can also be obtainedby solid phase chemistry.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae III, IIIa,IIIb, Illc, Illd, IV, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVk, IVm, IVn,V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX,XX, XXI, XXII, XXIII, XXIV, XXV, XXVI and XXVII wherein the ring A andthe groups G, G¹, L², L³, L¹¹, L¹², PG¹, PG², X, Y, Z, R²⁰ to R²³,R^(23a), R²³ b, R²³ c, R²⁴, R^(24a), R⁵⁰, R⁸⁰, R^(a) and R^(b) aredefined as above, in any of their stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, and their salts, and their use assynthetic intermediates or starting compounds. All general explanations,specifications of embodiments and definitions of numbers and groupsgiven above with respect to the compounds of the formula I applycorrespondingly to the said intermediates and starting compounds. Asubject of the invention are in particular the novel specific startingcompounds and intermediates described herein. Independently thereofwhether they are described as a free compound and/or as a specific salt,they are a subject of the invention both in the form of the freecompounds and in the form of their salts, and if a specific salt isdescribed, additionally in the form of this specific salt.

The compounds of the formula I inhibit the Edg-2 receptor (LPA₁receptor) as can be demonstrated in the pharmacological test describedbelow and in other tests which are known to a person skilled in the art.The compounds of the formula I and their physiologically acceptablesalts are valuable pharmaceutical active compounds. The compounds of theformula I and their physiologically acceptable salts can be used for thetreatment of cardiovascular diseases such as heart failure includingsystolic heart failure, diastolic heart failure, diabetic heart failureand heart failure with preserved ejection fraction, cardiomyopathy,myocardial infarction, myocardial remodeling including myocardialremodeling after infarction or after cardiac surgery, vascularremodeling including vascular stiffness, hypertension includingpulmonary hypertension, portal hypertension and systolic hypertension,atherosclerosis, peripheral arterial occlusive disease (PAOD),restenosis, thrombosis or vascular permeability disorders, forcardioprotection such as cardioprotection after myocardial infarction orafter cardiac surgery, for renoprotection, or for the treatment ofinflammation or inflammatory diseases such as rheumatoid arthritis,osteoarthritis, renal diseases such as renal papillary necrosis or renalfailure including renal failure after ischemia/reperfusion, pulmonarydiseases such as chronic obstructive pulmonary disease (COPD), asthma oracute respiratory dystress syndrome (ARDS), immunological diseases,allergic diseases, tumor growth, metastasis, metabolic diseases,fibrotic diseases such as pulmonary fibrosis including idiopathic lungfibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis,renal fibrosis including renal tubulointerstitial fibrosis, liverfibrosis, fibrosing skin conditions including keloid formation,collagenosis, scleroderma, progressive systemic sclerosis andnephrogenic fibrosing dermopathy, or other types of fibrosis includingDupuytren's contracture, psoriasis, pain such as neuropathic pain,diabetic pain or inflammatory pain, pruritus, retinalischemia/reperfusion damage, macular degeneration, psychiatricdisorders, neurodegenerative diseases, cerebral nerve disorders,peripheral nerve disorders, endocrinic disorders such ashyperthyroidism, scarring disorders or wound healing disorders, forexample. The treatment of diseases is to be understood as meaning boththe therapy of existing pathological changes or malfunctions of theorganism or of existing symptoms with the aim of relief, alleviation orcure, and the prophylaxis or prevention of pathological changes ormalfunctions of the organism or of symptoms in humans or animals whichare susceptible thereto and are in need of such a prophylaxis orprevention, with the aim of a prevention or suppression of theiroccurrence or of an attenuation in the case of their occurrence. Forexample, in patients who on account of their disease history aresusceptible to myocardial infarction, by means of the prophylactic orpreventive medicinal treatment the occurrence or re-occurrence of amyocardial infarction can be prevented or its extent and sequelaedecreased, or in patients who are susceptible to disturbed woundhealing, by means of the prophylactic or preventive medicinal treatmentwound healing after surgery can favorably be influenced. The treatmentof diseases can occur both in acute cases and in chronic cases. Theefficacy of the compounds of the formula I can be demonstrated in thepharmacological tests described below and in other tests which are knownto a person skilled in the art

The compounds of the formula I and their physiologically acceptablesalts can therefore be used in animals, in particular in mammals andspecifically in humans, as a pharmaceutical or medicament on their own,in mixtures with one another or in the form of pharmaceuticalcompositions. A subject of the present invention also are the compoundsof the formula I and their physiologically acceptable salts for use as apharmaceutical, as well as pharmaceutical compositions and medicamentswhich comprise an efficacious dose of at least one compound of theformula I and/or a physiologically acceptable salt thereof as an activeingredient and a pharmaceutically acceptable carrier, i.e. one or morepharmaceutically innocuous, or nonhazardous, vehicles and/or excipients,and optionally one or more other pharmaceutical active compounds. Asubject of the present invention furthermore are the compounds of theformula I and their physiologically acceptable salts for use in thetreatment of the diseases mentioned above or below, including thetreatment of any one of the mentioned diseases, for example heartfailure or fibrotic diseases such as pulmonary fibrosis, cardiacfibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis,liver fibrosis or fibrosing skin conditions, the use of the compounds ofthe formula I and their physiologically acceptable salts for themanufacture of a medicament for the treatment of the diseases mentionedabove or below, including the treatment of any one of the mentioneddiseases, for example heart failure or fibrotic diseases such aspulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascularfibrosis, renal fibrosis, liver fibrosis or fibrosing skin conditions,wherein the treatment of diseases comprises their therapy andprophylaxis as mentioned above, as well as their use for the manufactureof a medicament for the inhibition of the Edg-2 receptor (LPA₁receptor). A subject of the invention also are methods for the treatmentof the diseases mentioned above or below, including the treatment of anyone of the mentioned diseases, for example heart failure or fibroticdiseases such as pulmonary fibrosis, cardiac fibrosis, vascularfibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis orfibrosing skin conditions, which comprise administering an efficaciousamount of at least one compound of the formula I and/or aphysiologically acceptable salt thereof to a human or an animal which isin need thereof. The compounds of the formula I and pharmaceuticalcompositions and medicaments comprising them can be administeredenterally, for example by oral, sublingual or rectal administration,parenterally, for example by intravenous, intramuscular, subcutaneous orintraperitoneal injection or infusion, or by another type ofadministration such as topical, percutaneous, transdermal,intra-articular, intranasal or intraocular administration.

The compounds of the formula I and their physiologically acceptablesalts can also be used in combination with other pharmaceutical activecompounds, wherein in such a combination use the compounds of theformula I and/or their physiologically acceptable salts and one or moreother pharmaceutical active compounds can be present in one and the samepharmaceutical composition or in two or more pharmaceutical compositionsfor separate, simultaneous or sequential administration. Examples ofsuch other pharmaceutical active compounds are angiotensin convertingenzyme (ACE) inhibitors, ramipril, angiotensin II receptor subtype 1(AT1) antagonists, irbesartan, antiarrhythmics, dronedarone, peroxisomeproliferator-activated receptor-alpha (PPAR-α) activators, peroxisomeproliferator-activated receptor-gamma (PPAR-γ) activators, pioglitazone,rosiglitazone, prostanoids, endothelin receptor antagonists, bosentan,elastase inhibitors, calcium antagonists, beta blockers, diuretics,aldosterone receptor antagonists, eplerenone, renin inhibitors, rhokinase inhibitors, soluble guanylate cyclase (sGC) activators, sGCsensitizers, phosphodiesterase (PDE) inhibitors, phosphodiesterase type5 (PDE5) inhibitors, NO donors, digitalis drugs, angiotensin convertingenzyme/neutral endopeptidase (ACE/NEP) inhibitors, statins, bile acidreuptake inhibitors, platelet derived growth factor (PDGF) receptorantagonists, vasopressin antagonists, aquaretics, sodium hydrogenexchanger subtype 1 (NHE1) inhibitors, factor II/factor IIa antagonists,factor IX/factor IXa antagonists, factor X/factor Xa antagonists, factorXIll/factor XIIIa antagonists, anticoagulants, antithrombotics, plateletinhibitors, profibrinolytics, thrombin-activatable fibrinolysisinhibitors (TAFI), plasminogen activator inhibitor-1 (PAI 1), coumarins,heparins, thromboxane antagonists, serotonin antagonists, cyclooxygenaseinhibitors, acetylsalicylic acid, therapeutic antibodies, glycoproteinIIb/IIIa (GPIIb/llla) antagonists including abciximab, chymaseinhibitors, cytostatics, taxanes, paclitaxel, docetaxel, aromataseinhibitors, estrogen receptor antagonists, selective estrogen receptormodulators (SERM), tyrosine kinase inhibitors, imatinib, receptortyrosine kinase inhibitors, RAF kinase inhibitors, p38 mitogen-activatedprotein kinase (p38 MAPK) inhibitors, pirfenidone, multi-kinaseinhibitors, and sorafenib. A subject of the present invention also isthe said combination use of any one or more of the compounds of theformula I disclosed herein and their physiologically acceptable salts,with any one or more, for example one or two, of the mentioned otherpharmaceutical active compounds.

The pharmaceutical compositions and medicaments according to theinvention normally contain from about 0.5 to about 90 percent by weightof compounds of the formula I and/or physiologically acceptable saltsthereof, and an amount of active ingredient of the formula I and/or itsphysiologically acceptable salt which in general is from about 0.2 mg toabout 1000 mg, in particular from about 0.2 mg to about 500 mg, forexample from about 1 mg to about 300 mg, per unit dose. Depending on thekind of the pharmaceutical composition and other particulars of thespecific case, the amount may deviate from the indicated ones. Theproduction of the pharmaceutical compositions and medicaments can becarried out in a manner known per se. For this, the compounds of theformula I and/or their physiologically acceptable salts are mixedtogether with one or more solid or liquid vehicles and/or excipients, ifdesired also in combination with one or more other pharmaceutical activecompounds such as those mentioned above, and brought into a suitableform for dosage and administration, which can then be used in humanmedicine or veterinary medicine.

As vehicles, which may also be looked upon as diluents or bulkingagents, and excipients suitable organic and inorganic substances can beused which do not react in an undesired manner with the compounds of theformula I. As examples of types of excipients, or additives, which canbe contained in the pharmaceutical compositions and medicaments,lubricants, preservatives, thickeners, stabilizers, disintegrants,wetting agents, agents for achieving a depot effect, emulsifiers, salts,for example for influencing the osmotic pressure, buffer substances,colorants, flavorings and aromatic substances may be mentioned. Examplesof vehicles and excipients are water, vegetable oils, waxes, alcoholssuch as ethanol, isopropanol, 1,2-propanediol, benzyl alcohols,glycerol, polyols, polyethylene glycols or polypropylene glycols,glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose,carbohydrates such as lactose or starch like corn starch, sodiumchloride, stearic acid and its salts such as magnesium stearate, talc,lanolin, petroleum jelly, or mixtures thereof, for example saline ormixtures of water with one or more organic solvents such as mixtures ofwater with alcohols. For oral and rectal use, pharmaceutical forms suchas, for example, tablets, film-coated tablets, sugar-coated tablets,granules, hard and soft gelatin capsules, suppositories, solutions,including oily, alcoholic or aqueous solutions, syrups, juices or drops,furthermore suspensions or emulsions, can be used. For parenteral use,for example by injection or infusion, pharmaceutical forms such assolutions, for example aqueous solutions, can be used. For topical use,pharmaceutical forms such as ointments, creams, pastes, lotions, gels,sprays, foams, aerosols, solutions or powders can be used. Furthersuitable pharmaceutical forms are, for example, implants and patches andforms adapted to inhalation. The compounds of the formula I and theirphysiologically acceptable salts can also be lyophilized and theobtained lyophilizates used, for example, for the production ofinjectable compositions. In particular for topical application, alsoliposomal compositions are suitable. The pharmaceutical compositions andmedicaments can also contain one or more other active ingredientsand/or, for example, one or more vitamins.

As usual, the dosage of the compounds of the formula I depends on thecircumstances of the specific case and is adjusted by the physicianaccording to the customary rules and procedures. It depends, forexample, on the compound of the formula I administered and its potencyand duration of action, on the nature and severity of the individualsyndrome, on the sex, age, weight and the individual responsiveness ofthe human or animal to be treated, on whether the treatment is acute orchronic or prophylactic, or on whether further pharmaceutical activecompounds are administered in addition to a compound of the formula I.Normally, in the case of administration to an adult weighing about 75kg, a dose from about 0.1 mg to about 100 mg per kg per day, inparticular from about 1 mg to about 10 mg per kg per day (in each casein mg per kg of body weight), is sufficient. The daily dose can beadministered in the form of a single dose or divided into a number ofindividual doses, for example two, three or four individual doses. Theadministration can also be carried out continuously, for example bycontinuous injection or infusion. Depending on the individual behaviorin a specific case, it may be necessary to deviate upward or downwardfrom the indicated dosages.

Besides as a pharmaceutical active compound in human medicine andveterinary medicine, the compounds of the formula I can also be employedas an aid in biochemical investigations or as a scientific tool or fordiagnostic purposes, for example in in-vitro diagnoses of biologicalsamples, if an inhibition of the Edg-2 receptor is intended. Thecompounds of the formula I and their salts can also be used asintermediates for the preparation of further pharmaceutical activesubstances.

The following examples illustrate the invention.

Abbreviations

-   ACN acetonitrile-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DMF dimethylformamide-   DMSO dimethyl sulfoxide-   EA ethyl acetate-   EDIA N-ethyldiisopropylamine-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HEP heptane-   HOBT 1-hydroxy-benzotriazole-   TFA trifluoroacetic acid-   THF tetrahydrofuran

In general, reactions were carried out under argon. When examplecompounds containing a basic group were purified by preparative highpressure liquid chromatography (HPLC) on reversed phase (RP) columnmaterial and, as customary, the eluent was a gradient mixture of waterand acetonitrile containing trifluoroacetic acid, they were in partobtained in the form of their acid addition salts with trifluoroaceticacid, depending on the details of the workup such as evaporation orlyophilization conditions. In the names of the example compounds and thestructural formulae such contained trifluoroacetic acid is notspecified.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or thin layer chromatography (TLC)Rf values, and/or nuclear magnetic resonance (NMR) spectra. Unlessspecified otherwise, ¹H-NMR spectra were recorded at 500 MHz in D₆-DMSOas solvent at 298 K. In the NMR characterization, the chemical shift 6(in ppm), the number of hydrogen atoms (H) and the multiplicity (s:singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doubletsof doublets, t: triplet, dt: doublet of triplets, tt: triplet oftriplets, q: quartet, dq: doublet of quartets, m: multiplet; br: broad)of the peaks as determined on printouts are given. In the MScharacterization, in general the mass number (m/z) of the peak of themolecular ion [M], e.g. [M⁺], or of a related ion such as the ion[M+1]^(, e.g. [(M+)1)⁺], i.e. the protonated molecular ion[(M+H)⁺]abbreviated as [MH⁺], or the ion [M−1], e.g. [(M−1)⁻], i.e. thedeprotonated molecular ion [(M−H)⁻], which was formed depending on theionization method used, is given. Generally, the ionization method waselectrospray ionization (ESI). The particulars of the LC/MS methods usedare as follows.

Method LC1

Column: Merck Chromolith FastGradient RP-18e, 50×2 mm; flow: 2 ml/min;50° C.; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2%A+98% B for 0.2 min, then to 98% A+2% B within 2.2 min, then 98% A+2% Bfor 0.8 min; MS ionization method: ESI⁺

Method LC2

Column: Merck Chromolith FastGradient RP-18e, 50×2 mm; flow: 2.4 ml/min;50° C.; eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2%A+98% B for 0.2 min, then to 98% A+2% B within 2.2 min, then 98% A+2% Bfor 0.8 min; MS ionization method: ESI⁺

Method LC3

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1 ml/min; eluent A:methanol+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2% A+98% B for1 min, then to 95% A+5% B within 4 min, then 95% A+5% B for 1.25 min; MSionization method: ESI⁺

Method LC4

Column: Waters Acquity HPLC BEH C18, 50×2.1 mm; 1.7 μm; flow: 0.9ml/min; 55° C.; eluent A: ACN+0.08% formic acid; eluent B: water+0.1%formic acid; from gradient: 5% A+95% B to 95% A+5% B within 1.1 min,then 95% A+5% B for 0.6 min; MS ionization method: ESI⁺ or ESI⁻

Method LC5

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; eluentA: ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient:from 3% A+97% B to 60% A+40% B within 3.5 min, then to 98% A+2% B within0.5 min, then 98% A+2% B for 1 min; MS ionization method: ESI⁻

Method LC6

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; 45° C.;eluent A: ACN+0.1% formic acid; eluent B: water+0.1% formic acid;gradient: from 3% A+97% B to 60% A+40% B within 3.5 min, then to 98%A+2% B within 0.5 min, then 98% A+2% B for 1 min; MS ionization method:ESI⁺ or ESI⁻

Method LC7

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 40° C.;eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% Bfor 0.2 min, then to 95% A+5% B within 2.2 min, then 95% A+5% B for 0.8min; MS ionization method: ESI⁺

Method LC8

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.7 ml/min; 50° C.;eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% Bfor 0.2 min, then to 95% A+5% B within 2.2 min, then 95% A+5% B for 1.1min; MS ionization method: ESI⁺

Method LC9

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; 40° C.;eluent A: ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% Bfor 0.3 min, then to 95% A+5% B within 3.2 min, then 95% A+5% B for 0.5min; MS ionization method: ESI⁺

Method LC10

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2% A+98% B for 1min, then to 95% A+5% B within 4 min, then 95% A+5% B for 1.25 min; MSionization method: ESI⁺

Method LC11

Column: Thermo Javelin C18, 40×2.1 mm, 5 μm; flow: 1 ml/min; eluent A:ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 2% A+98% B to 80%A+20% B within 7 min, then to 100% A+0% B within 0.2 min; MS ionizationmethod: ESI⁺

Method LC12

Column: Zorbax Eclipse XDB-C18, 50×4.6 mm, 1.8 μm; flow: 1.5 ml/min; 40°C.; eluent A: ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 2%A+98% B to 100% A+0% B within 2 min; MS ionization method: ESI⁺

Method LC13

Column: YMC J'sphere H80, 20×2.1 mm, 4 μm; 30° C.; flow: 1.0 ml/min;eluent A: ACN; eluent B: water+0.05% TFA; gradient: from 4% A+96% B to95% A+5% B within 2.4 min, then to 4% A+96% B within 0.05 min, then 4%A+96% B for 0.05 min; MS ionization method: ESI⁺

EXAMPLE 11-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid

Step 1: 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoic acidmethyl ester

2-(2-Fluoro-5-methyl-phenyl)-ethanol (508 mg, 3.29 mmol) was dissolvedin THF (23 ml). Triphenylphosphine (1.08 g, 4.12 mmol) and3-hydroxy-4-methoxy-benzoic acid methyl ester (500 mg, 2.75 mmol) wereadded, the mixture was cooled in an ice bath, and DIAD (832 mg, 4.12mmol) was added slowly with stirring. The ice bath was removed andstirring was continued overnight at room temperature. The volatiles wereevaporated in vacuo, and the residue was purified by RP HPLC (water/ACNgradient) to give 530 mg of the title compound.

¹H-NMR: δ=7.59 (dd, 1H); 7.45 (d, 1H); 7.24 (d, 1H); 7.10-7.02 (m, 3H);4.20 (t, 2H); 3.82 (s, 3H); 3.80 (s, 3H); 3.04 (t, 2H); 2.26 (s, 3H)

Step 2: 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoic acid

The compound of step 1 (530 mg, 1.66 mmol) was dissolved in dioxane (8.3ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added andthe mixture was kept for 20 min at 60° C. After cooling, the mixture waspartitioned between an excess of 2 N hydrochloric acid and EA and theaqueous phase extracted with EA. The combined organic phases were driedover sodium sulfate, filtered and evaporated to dryness in vacuo. Theresidue was stirred overnight with a mixture of diethyl ether and HEP,filtered, and the solid was dried in vacuo to give 500 mg of the titlecompound.

¹H-NMR: δ=12.5 (br s, 1H); 7.56 (dd, 1H); 7.44 (d, 1H); 7.23 (d, 1H);7.10-7.02 (m, 3H); 4.20 (t, 2H); 3.82 (s, 3H); 3.04 (t, 2H); 2.26 (s,3H)

Step 3:1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid methyl ester

The compound of step 2 (285 mg, 0.937 mmol) was dissolved in an excessof thionyl chloride (0.7 ml) and stirred for 20 min at 60° C. Thesolution was evaporated to dryness in vacuo. The residue was dissolvedin a little DCM and added to a well-stirred mixture of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (195 mg,0.937 mmol), EA and an excess of a saturated aqueous sodiumhydrogencarbonate solution. The mixture was stirred for 30 min at roomtemperature. The layers were separated, the aqueous phase was extractedwith EA, the combined organic phases were washed with brine, dried oversodium sulfate, filtered and evaporated to dryness. This residue waspurified by preparative RP HPLC (water/ACN gradient) to give 160 mg ofthe title compound.

Step 4:1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid

The compound of step 3 (160 mg, 0.35 mmol) was dissolved in dioxane (1.8ml). 1 M aqueous lithium hydroxide (1.8 ml) was added, the mixture wasstirred at 60° C. for 30 min, cooled, and partitioned between 2 Nhydrochloric acid and EA. The aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate, filtered andevaporated to dryness. The residue was stirred in ether and the solidmaterial which formed was filtered and dried in vacuo to yield the titlecompound (126 mg).

¹H-NMR: δ=12 (br s, 1H); 8.07 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H); 7.24(d, 1H); 7.10-7.00 (m, 3H); 4.20 (t, 2H); 3.80 (s, 3H); 3.04 (t, 2H);2.26 (s, 3H); 2.13-2.01 (m, 4H); 1.58-1.42 (m, 8H)

EXAMPLE 21-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

Step 1: 4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid

From 3-hydroxy-4-methoxy-benzoic acid methyl ester, the title compoundwas obtained by reaction with 2-m-tolyl-ethanol(2-(3-methyl-phenyl)-ethanol) in analogy to step 1 of example 1 andhydrolysis of the ester group in analogy to step 2 of example 1.

¹H-NMR: δ=12.65 (br s, 1H); 7.56 (dd, 1H); 7.44 (d, 1H); 7.19 (t, 1H);7.17-7.15 (m, 1H); 7.12 (d, 1H); 7.06-7.02 (m, 2H); 4.19 (t, 2H); 3.83(s, 3H); 3.01 (t, 2H); 2.29 (s, 3H)

Step 2:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 1, steps 3 and4.

LC/MS (Method LC10): Rt=3.67 min; m/z=426.23 [MH⁺]

EXAMPLE 31-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid

Step 1: 1-(3-Acetoxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acidmethyl ester

3-Acetoxy-4-methoxy-benzoic acid (7.10 g, 33.8 mmol) was dissolved inDMF (70 ml). The solution was cooled in an ice bath and1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (7.72 g,37.2 mmol), EDIA (24.4 ml, 135 mmol) and TOTU (16.6 g, 50.7 mmol) wereadded sequentially. Stirring was continued at room temperature for 1 h.Water was added and stirring was continued for 1 h. The solid materialwhich formed was collected by filtration, washed with water and dried invacuo. The obtained material was stirred with a diethyl ether/HEPmixture, filtered and dried in vacuo to yield the title compound (9.03g).

¹H-NMR: δ=8.81 (s, 1H); 7.78 (dd, 1H); 7.62 (d, 1H); 7.19 (d, 1H); 3.82(s, 3H); 3.55 (s, 3H); 2.28 (s, 3H); 2.13-2.02 (m, 4H); 1.60-1.41 (m,8H)

Step 2: 1-(3-Hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acidmethyl ester

The compound of step 1 (10.6 g, 29.4 mmol) was dissolved in methanol(100 ml), potassium carbonate (812 mg, 5.88 mmol) was added and themixture was stirred overnight at room temperature. An excess of 2 Nhydrochloric acid was added, the methanol was evaporated in vacuo andthe residue partitioned between EA and water. The aqueous phase wasextracted with EA, the combined organic phases were dried over sodiumsulfate and evaporated to dryness to give the title compound (6.81 g).

¹H-NMR: δ=9.15 (s, 1H); 8.17 (s, 1H); 7.31 (dd, 1H); 7.28 (d, 1H); 6.95(d, 1H); 3.81 (s, 3H); 3.54 (s, 3H); 2.10-2.00 (m, 4H); 1.57-1.40 (m,8H)

Step 3:1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid methyl ester

The compound of step 2 (80 mg, 0.249 mmol) and triphenylphosphine (98mg, 0.374 mmol) were dissolved in THF.2-(5-Chloro-2-fluoro-phenyl)-ethanol (48 mg, 0.274 mmol) and DIAD (80.3mg, 0.374 mmol) were added and the mixture was stirred at roomtemperature for 2 h. The volatiles were evaporated in vacuo and theresidue was purified by preparative RP HPLC (water/ACN gradient) to give85 mg of the title compound.

¹H-NMR: δ=8.21 (s, 1H); 7.58 (dd, 1H); 7.51 (dd, 1H); 7.41 (d, 1H);7.38-7.33 (m, 1H); 7.25 (t, 1H); 7.02 (d, 1H); 4.23 (t, 2H); 3.80 (s,3H); 3.54 (s, 3H); 3.09 (t, 2H); 2.12-2.01 (m, 4H); 1.57-1.40 (m, 8H)

Step 4:1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylicacid

The compound of step 3 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

¹H-NMR: δ=8.07 (s, 1H); 7.58 (dd, 1H); 7.51 (dd, 1H); 7.42 (d, 1H);7.38-7.33 (m, 1H); 7.24 (t, 1H); 7.01 (d, 1H); 4.22 (t, 2H); 3.80 (s,3H); 3.10 (t, 2H); 2.12-2.02 (m, 4H); 1.59-1.42 (m, 8H)

In analogy to example 3, the example compounds of the formula I-1 listedin table 1 were prepared. The compounds can be named as1-[3-(R¹⁰¹-oxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid, forexample as1-{3-[2-(thiophen-3-yl)-ethoxy]-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid in the case of example 11.

TABLE 1 Example compounds of the formula I-1 Reten- tion Exam- LC/MS m/ztime ple R¹⁰¹ Method [MH⁺] [min] 4 2-(3,5-dimethyl-1H-pyrazol-4-yl)-LC10 430.18 2.57 ethyl 5 2-(2-fluoro-5-trifluoromethoxy- LC10 514.113.87 phenyl)-ethyl 6 2-(thiophen-2-yl)-ethyl LC8 418.17 2.36 72-(3-methoxy-phenyl)-ethyl LC8 442.23 2.39 8 2-phenyl-ethyl LC8 412.222.41 9 2-phenyl-propyl LC8 426.22 2.49 10 2-(3-chloro-phenyl)-ethyl LC8446.17 2.51 11 2-(thiophen-3-yl)-ethyl LC8 418.16 2.37 12(cyclohex-3-enyl)-methyl LC8 402.22 2.49 13 2-(2-fluoro-phenyl)-ethylLC8 430.17 2.41 14 2-phenyl-butyl LC8 440.21 2.59 152-(2,4-dichloro-phenyl)-ethyl LC8 480.11 2.66 162-(2-chloro-6-fluoro-phenyl)-ethyl LC8 464.12 2.50 172-(2,5-dichloro-phenyl)-ethyl LC8 480.1 2.62 182-(2,5-dimethyl-phenyl)-ethyl LC8 440.2 2.58 192-(2-methyl-phenyl)-ethyl LC8 426.2 2.49 202-(2,5-difluoro-phenyl)-ethyl LC8 448.15 2.42 212-(3-chloro-2-fluoro-phenyl)-ethyl LC8 464.13 2.51 22(3-phenyl-oxetan-3-yl)-methyl LC2 454.3 1.55

EXAMPLE 231-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclooctanecarboxylicacid

The title compound was synthesized in analogy to example 3 using1-amino-cyclooctanecarboxylic acid methyl ester hydrochloride instead of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): R_(t)=3.56 min; m/z=440.21 [MH⁺]

EXAMPLE 241-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cyclooctanecarboxylicacid

The title compound was synthesized in analogy to example 23.

LC/MS (Method LC9): Rt=3.58 min; m/z=458.2 [MH⁺]

EXAMPLE 254-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-oxepane-4-carboxylicacid

4-Amino-oxepane-4-carboxylic acid methyl ester hydrochloride(synthesized from oxepan-4-one via the Bucherer-Bergs hydantoin route inanalogy to the procedure described in J. W. Tsang et al., J. Med. Chem.27 (1984), 1663-1668; oxepan-4-one was synthesized fromtetrahydropyran-4-one by the in-situ diazomethane route described in F.Alonso et al., Tetrahedron 51 (1995), 10259-10280) was reacted with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid and the obtained methylester hydrolyzed in analogy to steps 3 and 4 of example 1.

¹H-NMR: δ=12.15 (br s, 1H); 8.19 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H);7.21-7.15 (m, 2H); 7.12 (d, 1H); 7.06-6.99 (m, 2H); 4.20 (t, 2H); 3.80(s, 3H); 3.65-3.55 (m, 4H); 3.01 (t, 2H); 2.35-2.22 (m, 5H, therein 2.29(s, 3H)); 2.15-2.01 (m, 2H); 1.81-1.71 (m, 1H); 1.65-1.57 (m, 1H)

By coupling 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid to therespective amino acid methyl ester via the carboxylic acid chlorideroute as described in step 3 of example 1 or the TOTU coupling route asdescribed in step 1 of example 3, the example compounds of the formulaI-2 listed in table 2 were prepared. The amino acid methyl esters or theamino acids were commercially available or were prepared from therespective ketone in analogy to example 25. In the formulae of thegroups R¹⁰² in table 2 the line crossed with the symbol

represents the free bond via which the group R¹⁰² is bonded to thenitrogen atom of the amide group depicted in formula I-2. I.e., in theformula of the complete molecule the terminal endpoint of the linecrossed with the said symbol ends on the nitrogen atom of the amidegroup.

TABLE 2 Example compounds of the formula I-2 Ex- ample

Starting material LC/MS Method m/z [MH⁺] Retention time [min] 26

(a) LC2 440.33 1.77 27

(a) LC10 426.14 3.72 28

(a) LC2 480.25 1.28 29

(a) LC10 454.39 3.99 30

(a) LC1 440.27 1.89 31

(a) LC2 438.31 1.29 32

(a) LC2 426.27 1.31 33

(a) LC2 412.26 1.29 34

(b) LC12 384.2 1.97 35

(b) LC12 398.2 2.02 36

(b) LC11 430.2 4.29 37

(b) LC11 414.2 3.7  38

(b) LC1 412.21 1.75 39

(b) LC1 466.17 1.87 40

(b) LC2 396.27 1.24 41

Example 42 LC2 398.29 1.25 (a) The amino acid ester was prepared fromthe respective ketone. (b) The amino acid ester or amino acid wascommercially available.

EXAMPLE 42 1-Amino-2-ethylcyclopropanecarboxylic acid ethyl ester(Starting Compound)

1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethylester (50 mg, 0.196 mmol) was dissolved in methanol (3 ml),azodicarboxylic acid dipotassium salt (D. J. Pasto et al., OrganicReactions 40 (1991), 91-155; 229 mg, 1.16 mmol) was added, the mixturewas cooled in an ice bath and acetic acid (141 mg, 2.35 mmol) was addedslowly. This mixture was warmed to 30° C. and stirred for 1 h. Theaddition of azodicarboxylic acid dipotassium salt and acetic acid andstirring at 30° C. was repeated until completion of the reduction. Themixture was evaporated to dryness and partitioned between EA and anaqueous sodium hydrogencarbonate solution. The aqueous phase wasextracted with EA, the combined organic phases were dried over sodiumchloride and evaporated to dryness. The residue was dissolved in amixture of DCM and TFA (1:1) and stirred for 1 h. The mixture wasevaporated to dryness and the obtained crude title compound (obtained inthe form of the trifluoroacetic acid salt) used in the amide couplingstep.

EXAMPLE 43trans-1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

Step 1:N-(trans-1-Cyano-4-methyl-cyclohexyl)-4-methoxy-3-(2-m-tolyl-ethoxy)-benzamide

4-Methyl-cyclohexanone was reacted in a Strecker aminonitrile synthesisin analogy to the procedure described in I. L. Munday, J. Chem. Soc.(1961), 4372-4379 to yieldtrans-1-amino-4-methyl-cyclohexanecarbonitrile which was coupled with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid via the TOTU coupling routeas described in step 1 of example 3.

¹H-NMR: δ=8.42 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H); 7.21-7.15 (m, 2H);7.12 (d, 1H); 7.04 (d, 2H); 4.19 (t, 2H); 3.81 (s, 3H); 3.02 (t, 2H);2.50-2.43 (m, 2H); 2.28 (s, 3H); 1.80-1.71 (m, 2H); 1.65-1.55 (m, 2H);1.48-1.38 (m, 1H); 1.27-1.14 (m, 2H); 0.91 (d, 3H)

Step 2:trans-1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid ethyl ester

The compound of step 1 (810 mg, 1.99 mmol) was dissolved in ethanol (10ml). The solution was cooled in an acetone/dry ice bath, acetyl chloride(2.3 ml, 30 mmol) was added and the mixture was warmed to roomtemperature and stirred for 3 days. Then 2 N hydrochloric acid was addedand the mixture was stirred overnight to hydrolyze the imino ester.After evaporation of the ethanol, the residue was partitioned between EAand 2 N hydrochloric acid. The phases were separated, the aqueous phasewas extracted with EA, the combined organic phases were dried oversodium sulfate and evaporated to dryness. The residue was purified bysilica gel chromatography (DCM/EA gradient) to yield the title compound(0.78 g).

¹H-NMR: δ=8.20 (s, 1H); 7.45 (dd, 1H); 7.39 (d, 1H); 7.22-7.15 (m, 2H);7.12 (d, 1H); 7.05-6.99 (m, 2H); 4.18 (t, 2H); 4.03 (q, 2H); 3.80 (s,3H); 3.01 (t, 2H); 2.31-2.25 (m, 5H, therein 2.29 (s, 3H)); 1.65-1.54(m, 4H); 1.52-1.41 (m, 1H); 1.30-1.18 (m, 2H); 1.10 (t, 3H); 0.88 (d,3H)

Step 3:trans-1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

¹H-NMR: δ=12.0 (s, 1H); 8.09 (s, 1H); 7.48 (dd, 1H); 7.40 (d, 1H);7.21-7.13 (m, 2H); 7.12 (d, 1H); 7.04 (d, 1H); 7.00 (d, 1H); 4.19 (t,2H); 3.80 (s, 3H); 3.02 (t, 2H); 2.32-2.22 (m, 5H, therein 2.29 (s,3H)); 1.65-1.51 (m, 4H); 1.51-1.40 (m, 1H); 1.31-1.20 (m, 2H); 0.86 (d,3H)

In analogy to example 43, by employing the respective ketone instead of4-methyl-cyclohexanone in the initial Strecker aminonitrile step, theexample compounds of the formula I-3 listed in table 3 were prepared. Inthe formulae of the groups R¹⁰³ in table 3 the line crossed with thesymbol

represents the free bond via which the group R¹⁰³ is bonded to thenitrogen atom of the amide group depicted in formula I-3. I.e., in theformula of the complete molecule the terminal endpoint of the linecrossed with the said symbol ends on the nitrogen atom of the amidegroup.

TABLE 3 Example compounds of the formula I-3 Example

LC/MS Method m/z [MH⁺] Retention time [min] 44

LC2 430.18 1.58 45

LC1 440.25 1.85 46

LC1 440.24 1.85 47

LC1 438.25 1.78 48

LC2 426.38 1.30 49

LC2 412.33 1.30 50

LC1 440.25 1.87 (a) Other diastereomer than in example 26, example 30,example 31 and example 32, respectively.

EXAMPLE 518-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.6]undecane-8-carboxylicacid

Step 1:8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acidand 1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid

8-Amino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid was synthesizedfrom 1,4-dioxa-spiro[4.6]undecan-8-one (F. Alonso et al., Tetrahedron 51(1995), 10259-10280) via the Bucherer-Bergs route in analogy to theprocedure described in J. W. Tsang et al., J. Med. Chem. 27 (1984),1663-1668. The intermediate was suspended in dioxane/water (2.5 ml/5ml), sodium carbonate (0.732 g, 6.90 mmol) was added, the mixture wascooled in an ice bath and benzyl chloroformate (0.392 ml, dissolved in2.5 ml of dioxane) was added with stirring. After 4 h, the mixture waspartitioned between 2 N hydrochloric acid and EA, the aqueous phase wasextracted with EA, the combined organic phrases were washed with water,dried over sodium sulfate and evaporated to dryness to yield a mixtureof 8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylicacid and 1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid.

Step 2:8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acidmethyl ester and 1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylicacid methyl ester

The mixture obtained in step 1 (200 mg) was dissolved in DMF (2 ml),cesium carbonate (280 mg, 0.86 mmol), EDIA (149 mg, 1.14 mmol) andiodomethane (121 mg, 0.858 mmol) were added and the mixture was stirredat room temperature for 2 h. The volatiles were evaporated in vacuo, theresidue was partitioned between EA and saturated aqueous sodiumhydrogencarbonate solution. The aqueous phase was extracted with EA, andthe combined organic phases were dried over sodium sulfate andevaporated to dryness. The residue was purified by RP HPLC (water/ACNgradient) to yield 66 mg of8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acidmethyl ester and 83 mg of1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester.

8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acidmethyl ester

¹H-NMR: δ=7.75 (s, 1H); 7.45-7.25 (m, 5H); 5.00 (s, 2H); 3.85-3.75 (m,4H); 3.56 (s, 3H); 2.5-1.4 (m, 10H)

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester

¹H-NMR: δ=7.76 (s, 1H); 7.40-7.28 (m, 5H); 5.02 (s, 2H); 3.60 (s, 3H);2.6-1.6 (m, 10 H)

Step 3: 8-Amino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methylester

66 mg of8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acidmethyl ester was dissolved in methanol and hydrogenated in an H-cube™hydrogenation reactor (ThalesNano, Budapest, Hungary) at a hydrogenpressure of 100 bar at 40° C. over a cartridge with 10% palladium oncharcoal. The mixture was evaporated to dryness to yield the crude titlecompound (32 mg).

Step 4:8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.6]undecane-8-carboxylicacid

The title compound was prepared from the compound of step 3 and4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to steps 3 and 4of example 1.

¹H-NMR: δ=12.1 (br s, 1H); 8.5-8.1 (br s, 1H); 7.45-7.33 (m, 2H);7.22-7.15 (m, 2H), 7.11 (d, 1H); 7.03 (d, 1H); 6.98 (d, 1H); 4.20 (t,2H); 3.84-3.76 (m, 7H); 3.01 (t, 2H), 2.29 (s, 3H); 2.27-1.90 (m, 4H);1.86-1.50 (m, 6 H)

EXAMPLE 521-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cycloheptanecarboxylicacid

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester(83 mg) was hydrogenated in analogy to step 3 of example 51 andtransformed into the title compound in analogy to step 4 of example 51.

¹H-NMR: δ=12.35 (s, 1H); 8.15 (s, 1H); 7.45 (dd, 1H); 7.39 (d, 1H);7.21-7.15 (m, 2H), 7.11 (d, 1H); 7.05-7.00 (m, 2H); 4.20 (t, 2H); 3.81(s, 3H); 3.01 (t, 2H), 2.65-2.50 (m, 2H); 2.42-2.11 (m, 8H, therein 2.30(s, 3H)); 1.92-1.69 (m, 3H)

EXAMPLE 534-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

Step 1:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cycloheptanecarboxylicacid methyl ester

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl esterwas hydrogenated in analogy to step 3 of example 51 and transformed intothe title compound by reaction with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 3 ofexample 1.

LC/MS (Method LC5): Rt=4.62 min; m/z=454.32 [MH⁺]

Step 2:4-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid methyl ester

The compound of step 1 (67 mg, 0.148 mmol) was dissolved in THF (1 ml)and cooled in an ice bath. Sodium borohydride (5.7 mg, 0.148 mmol) wasadded. Subsequently methanol (0.3 ml) was added dropwise. The ice bathwas removed and after stirring for 45 min at room temperature themixture was partitioned between EA and 2 N hydrochloric acid. Theaqueous phase was extracted with EA, and the combined organic phaseswere dried over sodium sulfate and evaporated to dryness to yield thetitle compound (65 mg).

LC/MS (Method LC6): Rt=4.27 min; m/z=456.36 [MH⁺]

Step 3:4-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 2 (63 mg, 0.138 mmol) was hydrolyzed in analogy tostep 4 of example 1 to yield the title compound (49 mg) as mixture ofdiastereomers.

¹H-NMR: δ=12.0 (s, 1H); 8.12/8.06 (2s, 1H); 7.49 (dd, 1H); 7.40 (d, 1H);7.22-7.10 (m, 3H), 7.08-6.99 (m, 2H); 4.46/4.40 (2d, 1H); 4.22-4.15 (m,2H); 3.80 (s, 3H); 3.67-3.58 (m, 1H); 3.01 (t, 2H); 2.28 (s, 3H);2.30-1.25 (m, 10H)

EXAMPLE 548-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.5]decane-8-carboxylicacid

The title compound was synthesized in analogy to example 51 startingfrom commercially available8-amino-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid.

LC/MS (Method LC1): Rt=1.63 min; m/z=470.2 [MH⁺]

EXAMPLE 551-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylicacid

Step 1:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylicacid methyl ester

8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.5]decane-8-carboxylicacid methyl ester (4.7 g, 9.7 mmol; intermediate in the synthesis ofexample 54) was dissolved in dioxane (70 ml), 2 N aqueous hydrochloricacid (10 ml) was added and the mixture was stirred at room temperatureovernight. The material was partitioned between EA and saturated aqueoussodium chloride solution, the aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate and evaporated todryness to yield the title compound.

LC/MS (Method LC1): Rt=1.66 min; m/z=440.21 [MH⁺]

Step 2:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylicacid

The compound of step 1 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

LC/MS (Method LC4): Rt=1.15 min; m/z=425.74 [MH⁺]

EXAMPLE 561-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylicacid

Step 1:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylicacid methyl ester

Methyltriphenylphosphonium bromide (4.88 g, 13.7 mmol) was suspended inTHF. Potassium bis(trimethylsilyl)amide (13.6 mmol, solution in toluene)was added slowly and the mixture was stirred at room temperature for 1h. The mixture was cooled in a acetone/dry ice bath and the compound ofstep 1 of example 55 (3.00 g, 6.83 mmol) was added. The mixture waswarmed to room temperature and stirred overnight. Methanol and anaqueous sodium dihydrogenphosphate solution were added. The mixture wasextracted with diethyl ether, the combined extracts were dried oversodium sulfate and evaporated to dryness. The residue was purified bysilica gel chromatography (HEP/EA gradient) to yield the title compound(1.40 g).

LC/MS (Method LC1): Rt=1.91 min; m/z=438.22 [MH⁺]

Step 2:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylicacid

The compound of step 1 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

LC/MS (Method LC10): Rt=3.70 min; m/z=424.25 [MH⁺]

EXAMPLE 576-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-spiro[2.5]octane-6-carboxylicacid

The compound of step 1 of example 56 (400 mg, 0.91 mmol) was dissolvedin toluene (8 ml) and diethylzinc (2.7 ml, 2.7 mmol, solution in hexane)was added. The mixture was heated to 60° C. and diiodomethane (1.10 g,4.11 mmol) was added with stirring. This mixture was reacted at 60° C.overnight, the addition of diethyl zinc and diiodomethane was repeatedand stirring continued for another night. The mixture was partitionedbetween EA and 2 N hydrochloric acid, the aqueous phase was extractedwith EA, the combined organic phases were washed with aqueous sodiumhydrogencarbonate solution, dried over sodium sulfate and evaporated todryness. The obtained methyl ester was hydrolyzed in analogy to step 4of example 1 to yield the title compound (15 mg).

LC/MS (Method LC10): Rt=3.70 min; m/z=438.29 [MH⁺]

EXAMPLE 584-Hydroxymethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

Step 1:4-Hydroxymethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid methyl ester

The compound of step 1 of example 56 (500 mg, 1.14 mmol) was dissolvedin THF (5 ml) and cooled to −25° C. Borane-tetrahydrofuran complex (2.29ml of a 1 M solution in THF, 2.29 mmol) was added and the mixture waskept overnight at 0° C. Hydrogen peroxide (2.5 ml, 30% in water) andsodium hydroxide (2.5 ml, 20% in water) were added sequentially andstirring was continued at room temperature. The mixture was partitionedbetween water and EA, the aqueous phase extracted with EA, and thecombined organic phases were dried over sodium sulfate and evaporated todryness. The residue was purified by silica gel chromatography (HEP/EAgradient) to yield the title compound.

LC/MS (Method LC1): Rt=1.62 min; m/z=456.18 [MH⁺]

Step 2:4-Hydroxymethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

The compound of step 1 was hydrolyzed in analogy to step 4 of example 1to yield the title compound as mixture of the cis isomer and the transisomer.

¹H-NMR: δ=12.0 (s, 1H); 8.09/7.96 (2s, 1H); 7.52-7.46 (m, 1H); 7.41 (s,1H); 7.22-7.16 (m, 2H); 7.12 (d, 1H); 7.08-6.98 (m, 2H); 4.42-4.36 (m,1H); 4.24-4.18 (m, 2H); 3.81 (s, 3H); 3.22/3.20 (2t, 2H); 3.01 (t, 2H);2.32-2.22 (m, 5H, therein 2.28 (s, 3H)); 1.68-1.50 (m, 4H); 1.48-1.33(m, 1H); 1.32-1.22 (m, 1H); 1.22-1.11 (m, 1H)

EXAMPLE 594-Fluoromethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

The compound of step 1 of example 58 (100 mg, 0.220 mmol) was dissolvedin DCM (2 ml), diethylaminosulfur trifluoride (35 mg, 0.22 mmol) wasadded and the mixture was stirred at room temperature for 72 h. Themixture was partitioned between EA and aqueous sodium hydrogencarbonatesolution. The aqueous phase was extracted with EA, the combined organicphases were dried over sodium sulfate and evaporated to dryness. Theresidue was purified by silica gel chromatography (HEP/EA gradient) andhydrolyzed in analogy to step 4 of example 1 to yield the titlecompound.

¹H-NMR: δ=12.15 (s, 1H); 8.15/8.02 (2s, 1H); 7.53-7.48 (m, 1H); 7.41 (s,1H); 7.23-7.16 (m, 2H); 7.12 (d, 1H); 7.09-7.00 (m, 2H); 4.35-4.26 (m,3H); 3.81 (s, 3H); 3.02 (t, 2H); 2.39-2.30 (m, 2H); 2.29 (s, 3H);1.80-1.53 (m, 5H); 1.48-1.22 (m, 2H)

EXAMPLE 601-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

Step 1: 1-(4-Acetyl-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acidmethyl ester

1-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (968 mg,4.66 mmol), HOBT (105 mg, 0.78 mmol) and 4-acetyl-3-hydroxy-benzoic acid(700 mg, 3.89 mmol) were dissolved in DMF (5 ml). EDIA (3.01 g, 23.3mmol) and EDC were added and the mixture was stirred at room temperaturefor 72 h. Then the mixture was partitioned between EA and saturatedsodium chloride solution, the aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate and evaporated todryness. The residue was purified by RP HPLC (water/ACN gradient) toyield the title compound.

LC/MS (Method LC9): Rt=3.19 min; m/z=334.17 [MH⁺]

Step 2:1-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid methyl ester

The compound of step 1 and 2-m-tolylethanol were reacted in analogy tostep 1 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt=3.98 min; m/z=452.21 [MH⁺]

Step 3:1-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

LC/MS (Method LC9): Rt=3.53 min; m/z=438.18 [MH⁺]

EXAMPLE 611-[4-(1-Hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of example 60 (300 mg, 0.686 mmol) was dissolved inmethanol (6 ml) and cooled in an ice bath. Sodium borohydride (79 mg,2.06 mmol) was added, the mixture was kept at 0° C. for 72 h, and thenevaporated to dryness. The residue was partitioned between EA and 2 Nhydrochloric acid, the aqueous phase was extracted with EA, the combinedorganic phases were dried over sodium sulfate and evaporated to dryness.The residue was stirred with diethyl ether and the solidified materialwas filtered and dried in vacuo to yield the title compound (50 mg).From the mother liquor a further batch of the title compounds wasisolated by RP HPLC (water/ACN gradient).

LC/MS (Method LC9): Rt=3.32 min; m/z=440.23 [MH⁺]

EXAMPLE 621-[4-Ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of example 61 (100 mg) was dissolved in ethanol (10 ml) andhydrogenated in an H-cube™ hydrogenation reactor at a hydrogen pressureof bar at 35° C. over a cartridge with 10% palladium on charcoal. Thereaction mixture was evaporated to dryness and purified by RP HPLC(water/ACN gradient) to yield the title compound (60 mg).

¹H-NMR: δ=12.00 (s, 1H); 8.12 (s, 1H); 7.38 (dd, 1H); 7.32 (d, 1H);7.22-7.13 (m, 3H); 7.11 (d, 1H); 7.03 (d, 1H); 4.23 (t, 2H); 3.03 (t,2H); 2.53 (q, 2H); 2.28 (s, 3H); 2.10-2.04 (m, 4H); 1.57-1.43 (m, 8H);1.03 (t, 3H)

EXAMPLE 631-[4-(1-Fluoro-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 2 of example 60 (110 mg, 0.244 mmol) was dissolvedin methanol (1.1 ml) and cooled in an ice bath. Sodium borohydride (9.2mg, 0.244 mmol) was added and stirring continued for 1 h. This mixturewas partitioned between EA and saturated sodium hydrogencarbonatesolution, the aqueous phase was extracted with EA, the combined organicphases were dried over sodium sulfate and evaporated to dryness. Theresidue (100 mg) was dissolved in DCM (2 ml) and diethylaminosulfurtrifluoride (36 mg, 0.22 mmol) was added. The mixture was stirred for 3h, partitioned between EA and saturated sodium hydrogencarbonatesolution, the aqueous phase was extracted with EA, the combined organicphases were dried over sodium sulfate and evaporated to dryness. Theobtained ester was hydrolyzed in analogy to step 4 of example 1 to yieldthe title compound.

¹H-NMR: δ=12.05 (s, 1H); 8.24 (s, 1H); 7.48 (d, 1H); 7.41-7.36 (m, 2H);7.20 (t, 1H); 7.15 (s, 1H); 7.12 (d, 1H); 7.03 (d, 1H); 5.81 (dq, 1H);4.28 (t, 2H); 3.03 (t, 2H); 2.30 (s, 3H); 2.12-2.02 (m, 4H); 1.56-1.42(m, 8H); 1.40 (dd, 3H)

EXAMPLE 641-[4-Chloro-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

Step 1: 3-Acetoxy-4-chlorobenzoic acid

4-Chloro-3-hydroxybenzoic acid (1.00 g, 5.80 mmol) was suspended inacetic anhydride (11 ml) and heated to reflux for 3 h. After cooling,water (11 ml) was added and the mixture was refluxed again for 1 h.After cooling, crystals formed overnight which were collected by suctionfiltration and dried in vacuo to yield the title compound (630 mg).

¹H-NMR: δ=13.5 (br s, 1H); 7.88-7.81 (m, 2H); 7.71 (d, 1H); 2.34 (s, 3H)

Step 2: 1-(3-Acetoxy-4-chloro-benzoylamino)-cycloheptanecarboxylic acidmethyl ester

The compound of step 1 (200 mg, 0.932 mmol) was dissolved in DCM (16ml), DMF (12 mg) and oxalyl chloride (362 mg, 2.80 mmol) were added andthe mixture was stirred at room temperature until completion of thereaction. The volatiles were evaporated in vacuo and the residuedissolved in DCM. The solution was added to a stirred mixture of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (194 mg,0.932 mmol) in EA/saturated sodium hydrogencarbonate solution withcooling in an ice bath. Stirring continued at room temperature for 2 h.The phases were separated, aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate and evaporated todryness. The residue was purified by silica gel chromatography (HEP/EAgradient) to yield the title compound (430 mg).

LC/MS (Method LC9): Rt=3.48 min; m/z=368.12 [MH⁺]

Step 3: 1-(4-Chloro-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acidmethyl ester

The compound of step 2 (400 mg, 1.088 mmol) was dissolved in methanol(3.5 ml), potassium carbonate (3 mg, 0.02 mmol) was added, and themixture was stirred at room temperature for 6 h and evaporated todryness to yield the title compound (300 mg).

LC/MS (Method LC9): Rt=3.05 min; m/z=326.22 [MH⁺]

Step 4:1-[4-Chloro-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 3 was etherified with 2-m-tolylethanol in analogyto step 1 of example 1, and the intermediate was hydrolyzed in analogyto step 4 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt=3.78 min; m/z=430.16 [MH⁺]

EXAMPLE 651-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 64 startingwith 4-bromo-3-hydroxybenzoic acid in step 1.

LC/MS (Method LC9): Rt=3.83 min; m/z=474.11 [MH⁺]

EXAMPLE 662-Benzyloxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylicacid, Diastereomer 1 and Diastereomer 2

Step 1: 1-Amino-2-benzyloxy-cyclopentanecarbonitrile, Diastereomer 1 andDiastereomer 2

2-Benzyloxycyclopentanone (A. B. Smith et al., J. Am. Chem. Soc. 108(1986), 3040-3048; 310 mg, 1.63 mmol) was reacted in a Streckeraminonitrile synthesis in analogy to step 1 of example 43 to give thetwo racemic diastereomers of the title compound which were separated bysilica gel chromatography (HEP/EA gradient).

Diastereomer 1

¹H-NMR: δ=7.40-7.32 (m, 4H); 7.31-7.25 (m, 1H); 4.60 (d, 1H); 4.56 (d,1H); 3.75-3.72 (m, 1H); 2.07-1.92 (m, 2H); 1.83-1.77 (m, 1H); 1.77-1.67(m 3H)

Diastereomer 2

¹H-NMR: δ=7.40-7.32 (m, 4H); 7.31-7.25 (m, 1H); 4.68 (d, 1H); 4.61 (d,1H); 4.02 (dd, 1H); 1.98-1.62 (m, 5H); 1.62-1.51 (m, 1H)

Step 2a:2-Benzyloxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylicacid, Diastereomer 1

The compound of step 1, diastereomer 1, was coupled with4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid via the carboxylic acidchloride in analogy to step 3 of example 1. The obtained nitrile wasreacted with ethanol in analogy to step 2 of example 43, and theobtained ethyl ester was hydrolyzed in analogy to step 4 of example 1 toyield the title compound.

LC/MS (Method LC6): Rt=4.81 min; m/z=502.16 [M−H⁺]

Step 2b:2-Benzyloxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylicacid, Diastereomer 2

The compound of step 1, diastereomer 2, was reacted in analogy to step2a to yield the title compound.

LC/MS (Method LC1): Rt=1.91 min; m/z=504.18 [MH⁺]

EXAMPLE 672-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylicacid, Diastereomer 1 and Diastereomer 2

Diastereomer 1 and diastereomer 2 of the compound of example 66 wereseparately dissolved in ethanol and hydrogenated with palladium 10% oncharcoal at room temperature with 1 bar hydrogen pressure untilcompletion of the reaction. After filtration, the solutions wereevaporated to dryness and the residues purified by RP HPLC (water/ACNgradient) to yield the two diastereomers of the title compoundseparately.

Diastereomer 1

¹H-NMR: δ=8.52 (br s, 1H); 7.36-7.30 (m, 1H); 7.22-7.15 (m, 2H); 7.12(d, 1H); 7.06-7.00 (m, 2H); 4.60 (brs, 1H); 4.18 (t, 2H); 4.14-4.09 (m,1H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.20-2.11 (m, 1H);2.09-1.93 (m, 2H); 1.77-1.65 (m, 2H); 1.62-1.52 (m, 1H)

Diastereomer 2

¹H-NMR: δ=12.0 (br s, 1H); 8.11 (s, 1H); 7.45 (dd, 1H); 7.40 (d, 1H);7.23-7.14 (m, 2H); 7.11 (d, 1H); 7.06-7.00 (m, 2H); 5.11 (br s, 1H);4.29 (t, 1H); 4.19 (t, 2H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H);2.03-1.95 (m, 1H); 1.94-1.85 (m, 1H); 1.80-1.68 (m, 1H); 1.58-1.50 (m,2H)

EXAMPLE 682-Methoxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylicacid

The title compound was synthesized in analogy to example 60 startingwith 2-methoxy-cyclopentanone (B. Foehlisch et al., Chem. Ber. 120(1987), 1951-1960) and obtained as a mixture of diastereomers which wasnot separated.

LC/MS (Method LC4): Rt=1.21 min; m/z=428.25 [MH⁺]

EXAMPLE 691-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

Step 1: 3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester and2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester

3-Acetoxy-4-methoxybenzoic acid methyl ester (WO 2005/009389; 3.58 g,16.0 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®; 14.1 g, 39.9 mmol) were suspendedin ACN (50 ml) and heated in a microwave oven for 7 min at 170° C. Aftercooling, water was added and the mixture was repeatedly extracted withdiethyl ether. The combined extracts were dried over sodium sulfate andevaporated to dryness. The residue was purified by RP HPLC (water/ACNgradient). The obtained mixture of fluorinated species, which werepartially deacetylated, was dissolved in methanol (20 ml), potassiumcarbonate (80 mg) was added and the mixture was stirred for 3 h at 60°C. The methanol was evaporated, the residue was partitioned between EAand 2 N hydrochloric acid, the aqueous phase was extracted with EA, thecombined organic phases were dried over sodium sulfate and evaporated todryness. This residue was purified by RP HPLC (water/ACN gradient) toyield two regioisomers.

3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester

¹H-NMR: δ=10.2 (s, 1H); 7.30 (d, 1H); 7.21 (dd, 1H); 3.88 (s, 3H); 3.81(s, 3H)

2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester

¹H-NMR: δ=10.55 (s, 1H); 7.61 (d, 1H); 6.80 (dd, 1H); (d, 1H); 3.94 (d,3H); 3.84 (s, 3H); 2.32 (s, 3H)

Step 2:1-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was coupled to2-m-tolylethanol, the intermediate hydrolyzed, coupled to1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride and theobtained ester hydrolyzed in analogy to steps 1 to 4 of example 1 toyield the title compound.

LC/MS (Method LC7): Rt=2.74 min; m/z=444.24 [MH⁺]

EXAMPLE 701-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to step 2 of example 69from 3-fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester (prepared instep 1 of example 69).

LC/MS (Method LC7): Rt=2.64 min; m/z=444.22 [MH⁺]

EXAMPLE 711-[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid

Step 1: Trifluoromethanesulfonic acid 2,2-difluoro-2-phenyl-ethyl ester

2,2-Difluoro-2-phenyl-ethanol (200 mg, 1.27 mmol) was dissolved in DCM(2 ml) and treated at 0° C. with EDIA (0.27 ml, 1.52 mmol) andtrifluoromethanesulfonic acid anhydride (0.43 g, 1.52 mmol). Aftercompletion of the reaction (monitored by TLC (silica gel, DCM/methanol98:2)), the mixture was partitioned between water and EA. The aqueousphase was extracted with EA, the combined organic phases were washedwith saturated sodium chloride solution, dried over sodium sulfate andevaporated to dryness. This intermediate was used without furtherpurification.

Step 2:1-[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid methyl ester

To a mixture of1-(3-hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methylester (80 mg, 0.249 mmol) and potassium carbonate (83 mg, 0.60 mmol) in0.5 ml of acetone and 0.5 ml of DMF was added slowly a solution of thecompound of step 1 (0.22 g, 0.374 mmol) as solution in acetone. Themixture was stirred for 3 d at room temperature and then evaporated. Theresidue was purified by preparative RP HPLC (water/ACN gradient) to givethe title compound (87 mg).

LC/MS (Method LC10): Rt=3.90 min; m/z=462.12 [MH⁺]

Step 3:1-[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1to yield the title compound.

LC/MS (Method LC8): Rt=2.41 min; m/z=448.19 [MH⁺]

EXAMPLE 721-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-cycloheptanecarboxylicacid

Step 1:1-[3-(1,3-Dihydroxy-3-m-tolyl-propyl)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid methyl ester

3-Acetyl-4-methoxy-benzoic acid methyl ester (150 mg, 0.720 mmol) wasdissolved in THF (3 ml), cooled to −78° C., and a freshly preparedsolution of lithium diisopropylamide (obtained by addition ofn-butyllithium in n-hexane (0.317 ml, 2.5 M solution) todiisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at 0° C. andstirring for 10 min) was slowly added with stirring. After 10 min,3-methylbenzaldehyde (86.5 mg, 0.720 mmol) was added at −78° C. After 30min at −78° C., 2 N hydrochloric acid and EA were added, the coolingbath was removed, the mixture was brought to room temperature. Thephases were separated, the aqueous phase was extracted three times withEA, the combined organic phases were dried over sodium chloride,decanted and evaporated to dryness. The residue was dissolved inmethanol (5 ml), sodium borohydride (28.7 mg, 0.761 mmol) was added, andthe mixture was stirred at room temperature for 30 min. The mixture wasevaporated to dryness and the residue was purified by silica gelchromatography (HEP/EA gradient) to give 140 mg of the title compound asa mixture of diastereomers.

LC/MS (Method LC13): Rt=1.32 min; m/z=353.1 [MNa⁺], 683.2 [2MNa⁺]

Step 2: 4-Methoxy-3-(3-m-tolyl-propyl)-benzoic acid methyl ester

The compound of step 1 (140 mg, 0.424 mmol) was dissolved in ethanol (10ml), 12 N hydrochloric acid (0.2 ml) and palladium on charcoal (10%) wasadded, and the mixture was hydrogenated at a hydrogen pressure of 6 barat room temperature overnight. After filtration and evaporation, theresidue was purified by silica gel chromatography (HEP/EA gradient) togive 80 mg of the title compound.

¹H-NMR: δ=7.83 (dd, 1H); 7.72 (d, 1H); 7.16 (dd, 1H); 7.06 (d, 1H);7.03-6.96 (m, 3H); 3.85 (s, 3H); 3.80 (s, 3H); 2.65-2.53 (m, 4H); 2.27(s, 3H); 1.82 (m, 2H)

Step 3:1-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-cycloheptanecarboxylicacid

From the compound of step 2, the title compound was obtained byhydrolysis of the ester group in analogy to example 1 step 2, reactionof the obtained carboxylic acid with 1-amino-cycloheptanecarboxylic acidmethyl ester hydrochloride in analogy to step 3 of example 1, andhydrolysis of the ester group in analogy to step 4 of example 1.

¹H-NMR: δ=11.95 (br s, 1H); 8.03 (s, 1H); 7.73 (dd, 1H); 7.64 (d, 1H);7.14 (t, 1H); 7.03-6.95 (m, 4H); 3.83 (s, 3H); 2.63-2.55 (m, 4H); 2.27(s, 3H); 2.12-2.03 (m, 4H); 1.83 (tt, 2H); 1.56-1.45 (m 8H)

EXAMPLE 731-[3-(2-Hydroxy-2-m-tolyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid

Step 1: 4-Methoxy-3-(2-oxo-2-m-tolyl-ethoxy)-benzoic acid methyl ester

3-Hydroxy-4-methoxybenzoic acid methyl ester (2.50 g, 13.7 mmol) wasdissolved in methanol (20 ml), potassium carbonate (3.72 g, 27.4 mmol)and 2-bromo-1-m-tolyl-ethanone (2.92 g, 13.7 mmol) were added and themixture was stirred overnight at room temperature. The volatiles wereevaporated, the crude material was partitioned between EA and water, theaqueous phase was extracted with EA, the combined organic phases weredried over sodium sulfate and evaporated to dryness. The residue waspurified by preparative RP HPLC (water/ACN gradient) to yield the titlecompound.

LC/MS (Method LC2): Rt=1.57 min; m/z=315.17 [MH⁺]

Step 2:1-[4-Methoxy-3-(2-oxo-2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid ethyl ester

The compound of step 2 was hydrolyzed in analogy to step 2 of example 1,and the carboxylic acid intermediate was coupled to1-amino-cycloheptanecarboxylic acid ethyl ester hydrochloride in analogyto step 1 of example 3 to yield the title compound.

LC/MS (Method LC2): Rt=1.74 min; m/z=468.23 [MH⁺]

Step 3:1-[3-(2-Hydroxy-2-m-tolyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylicacid

The compound of step 2 was reduced with sodium borohydride in analogy tostep 2 of example 53, the ester intermediate purified by RP HPLC(water/ACN gradient) and hydrolyzed in analogy to step 4 of example 1 toyield the title compound.

LC/MS (Method LC2): Rt=1.51 min; m/z=442.29 [MH⁺]

EXAMPLE 741-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohept-4-enecarboxylicacid

1-Amino-cyclohept-4-enecarboxylic acid methyl ester (K. Hammer et al.,Tetrahedron 53 (1997), 2309-2322) was coupled to4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid analogy to step 1 of example3. The ester intermediate was hydrolyzed in analogy to step 4 of example1 to yield the title compound.

LC/MS (Method LC1): Rt=1.76 min; m/z=424.29 [MH⁺]

EXAMPLE 754-[4-Methyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-bicyclo[5.1.0]octane-4-carboxylicacid

1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohept-4-enecarboxylicacid methyl ester (0.418 g, 0.955 mmol) was dissolved in toluene (4.5ml), diethylzinc (2.86 mmol, 1.5 M solution in toluene) was added andthe mixture was warmed to 60° C. Diiodomethane (1.16 g, 4.30 mmol) wasadded dropwise and the mixture was stirred overnight at 60° C. Theaddition of diethyl zinc and diiodomethane was repeated until completionof the reaction. The mixture was partitioned between EA and 2 Nhydrochloric acid, the aqueous phase extracted with EA, and the combinedorganic phases were dried over sodium sulfate and evaporated to dryness.The obtained ester was hydrolyzed in analogy to step 4 of example 1. Thetitle compound was purified by preparative RP HPLC (water/ACN gradient).

LC/MS (Method LC4): Rt=1.32 min; m/z=438.35 [MH⁺]

EXAMPLE 761-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-3-methyl-cyclobutanecarboxylicacid

Step 1: 1-Amino-3-methyl-cyclobutanecarboxylic acid ethyl esterhydrochloride

3-Methyl-cyclobutane-1,1-dicarboxylic acid ethyl ester (V. Prelog etal., Helv. Chim. Acta 65 (1982), 2622-2644; 200 mg, 1.074 mmol) wassuspended in acetone (20 ml) and stirred in an ice bath. Triethylamine(152 mg, 1.50 mmol) and isobutyl chloroformate (191 mg, 1.40 mmol) wereadded, the mixture was stirred at 0° C. for min, then sodium azide (129mg, 1.99 mmol) as solution in water (10 ml) was added, and stirring wascontinued for 15 min. Then diethyl ether (50 ml) was added, the phaseswere separated. The organic layer was washed with water, dried oversodium sulfate, filtered and added to refluxing toluene in a flask withdistillation bridge. The toluene solution was refluxed for 4 h, thevolatiles were evaporated in vacuo, the residue was dissolved indioxane, 2 N hydrochloric acid was added in excess, and the mixture wasstirred until the isocyanate was completely decomposed (approximately 20min). The volatiles were evaporated and the obtained amino acid esterhydrochloride was used without further purification.

Step 2:1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-3-methyl-cyclobutanecarboxylicacid

The compound of step 1 (65 mg, 0.413 mmol) was coupled to4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 ofexample 3. The ester intermediate was hydrolyzed in analogy to step 4 ofexample 1 to yield the title compound as mixture of the cis isomer andthe trans isomer.

¹H-NMR: δ=12.2 (s, 1H); 8.75/8.70 (2 s, 1H); 7.55-7.45 (m, 2H);7.23-7.11 (m, 3H); 7.08-6.98 (m, 2H); 4.23-4.14 (m, 2H); 3.81 (2s, 3H);3.02 (t, 2H); 2.73-2.68 (m, 1H); 2.55-2.25 (m, 5H, therein 2.29 (s,3H)); 2.20-2.12 (m, 1H); 1.90-1.80 (m, 1H); 1.05 (d, 3H)

EXAMPLE 771-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

6-Chloro-5-nitro-nicotinic acid methyl ester was prepared according tothe procedure described in WO 2005/021544 and transformed into5-hydroxy-6-methoxy-nicotinic acid methyl ester according to theprocedure described in WO 95/04045. The intermediate was transformedinto the title compound by etherification with 2-m-tolyl-ethanol inanalogy to step 1 of example 1, hydrolysis of the ester group in analogyto step 2 of example 1, reaction of the obtained carboxylic acid with1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride inanalogy to step 3 of example 1 and hydrolysis in analogy to step 4 ofexample 1.

¹H-NMR: δ=12.0 (s, 1H); 8.21 (d, 1H); 8.20 (s, 1H); 7.63 (d, 1H);7.23-7.17 (m, 2H); 7.12 (d, 1H); 7.03 (d, 1H); 4.23 (t, 2H); 3.91 (s,3H); 3.02 (t, 2H); 2.29 (s, 3H); 2.13-2.00 (m, 4H); 1.55-1.45 (m, 8H)

EXAMPLE 781-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cyclooctanecarboxylicacid

The title compound was synthesized in analogy to example 77 using1-amino-cyclooctanecarboxylic acid methyl ester hydrochloride instead of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): Rt=3.66 min; m/z=441.19 [MH⁺]

EXAMPLE 79cis-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 usingcis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride (prepared in analogy to example 25) instead of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

¹H-NMR: δ=12.2 (s, 1H); 8.23 (s, 1H); 8.11 (s, 1H); 7.61 (s, 1H);7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.03 (d, 1H); 4.26 (t, 2H); 3.91 (s,3H); 3.02 (t, 2H); 2.30-2.22 (m, 5H, therein 2.28 (s, 3H)); 1.70-1.61(m, 2H); 1.54-1.48 (m, 2H); 1.42-1.32 (m, 1H); 1.25-1.12 (m, 2H); 0.88(d, 3H)

EXAMPLE 80trans-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 usingtrans-1-amino-1-cyclohexanecarbonitrile (step 1 of example 43) insteadof 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride andhydrolysis of the carbonitrile in analogy to example 43, steps 2 and 3.

¹H-NMR: δ=12.1 (s, 1H); 8.22 (s, 1H); 8.20 (s, 1H); 7.62 (s, 1H);7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.05 (d, 1H); 4.22 (t, 2H); 3.91 (s,3H); 3.04 (t, 2H); 2.31-2.24 (m, 5H, therein 2.28 (s, 3H)); 1.62-1.53(m, 4H); 1.51-1.40 (m, 1H); 1.32-1.22 (m, 2H); 0.88 (d, 3H)

EXAMPLE 81trans-1-({5-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using2-(5-chloro-2-fluoro-phenyl)-ethanol in the etherification step.

LC/MS (Method LC1): Rt=1.81 min; m/z=464.16 [MH⁺]

EXAMPLE 82trans-1-({5-[2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using2-(2-fluoro-5-trifluoromethoxy-phenyl)-ethanol in the etherificationstep.

LC/MS (Method LC4): Rt=1.31 min; m/z=513.76 [MH⁺]

EXAMPLE 83trans-1-{[6-Methoxy-5-(2-phenyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using2-phenyl-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.27 min; m/z=413.24 [MH⁺]

EXAMPLE 84trans-1-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using2-(2,5-dimethyl-phenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.34 min; m/z=441.26 [MH⁺]

EXAMPLE 85trans-1-({5-[2-(3-chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using2-(3-chloro-phenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.31 min; m/z=447.18 [MH⁺]

EXAMPLE 86cis-1-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 79 using2-(2,5-dimethyl-phenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.34 min; m/z=441.3 [MH⁺]

EXAMPLE 871-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-(2,5-dimethyl-phenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.33 min; m/z=439.29 [M−H⁺]

EXAMPLE 881-{[5-(2-Phenyl-ethoxy)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-phenyl-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.26 min; m/z=413.3 [MH⁺]

EXAMPLE 89trans-4-tert-Butyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 80 using1-amino-4-tert-butyl-cyclohexanecarbonitrile in the amide coupling step.

LC/MS (Method LC4): Rt=1.36 min; m/z=469.4 [MH⁺]

EXAMPLE 90trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

5-Hydroxy-6-methoxy-nicotinic acid methyl ester was etherified with2-[3-(2-hydroxy-ethyl)-phenyl]-ethanol in analogy to step 1 ofexample 1. Hydrolysis of the ester group in analogy to step 2 of example1, coupling of the obtained carboxylic acid totrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3 and hydrolysis of themethyl ester in analogy to step 4 of example 1 yielded the titlecompound.

LC/MS (Method LC1): Rt=1.53 min; m/z=457.24 [MH⁺]

EXAMPLE 91cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 90 usingcis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-methyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.16 min; m/z=457.37 [MH⁺]

EXAMPLE 921-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

Step 1: 5-Bromo-6-methoxy-nicotinic acid

5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson et al., J.Org. Chem. 49 (1984), 5237-5243; 2.00 g, 8.13 mmol) was dissolved indioxane (40 ml), lithium hydroxide (40 ml of a 1 M solution in water)was added and subsequently sufficient methanol to achieve completedissolution. The mixture was stirred at 60° C. for 2 h.

The methanol was evaporated in vacuo and the remaining mixture wasacidified with 2 N hydrochloric acid and extracted with EA. The combinedextracts were dried over sodium sulfate, filtered and evaporated todryness to yield the title compound.

¹H-NMR: δ=13.3 (s, 1H); 8.68 (d, 1H); 8.35 (d, 1H); 4.01 (s, 3H)

Step 2:1-{[5-Bromo-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid methyl ester

The compound of step 1 (1.85 g, 7.97 mmol) was dissolved in thionylchloride (6 ml) and stirred for 30 min at 60° C. The volatiles wereevaporated in vacuo, the residue was dissolved in DCM and added to astirred mixture of 1-amino-cycloheptanecarboxylic acid methyl esterhydrochloride, EA and saturated sodium hydrogencarbonate solution withice cooling. The mixture was stirred at room temperature overnight, thephases were separated and the aqueous phase was extracted with EA. Thecombined organic phases were dried over sodium sulfate and evaporated todryness to yield the title compound (2.80 g).

¹H-NMR: δ=8.62 (d, 1H); 8.52 (s, 1H); 8.48 (d, 1H); 3.99 (s, 3H); 3.57(s, 3H); 2.15-2.01 (m, 4H); 1.65-1.43 (m, 8H)

Step 3:1-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid methyl ester

The compound of step 2 (300 mg, 0.779 mmol), 3-cyano-phenylboronic acid(171 mg, 1.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (214 mg,0.234 mmol), potassium fluoride (149 mg, 2.57 mmol) andtri-tert-butylphosphonium tetrafluoroborate (136 mg, 0.47 mmol) in aflask were thoroughly flushed with argon, dioxane (3 ml) was added andthe mixture was stirred for 2 h at 50° C. The mixture was filtered oversilica gel and evaporated to dryness. This residue was purified by RPHPLC (water/ACN gradient) to yield 200 mg of the title compound.

LC/MS (Method LC9): Rt=3.44 min; m/z=408.6 [MH⁺]

Step 4:1-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

The compound of step 3 was hydrolyzed in analogy to step 4 of example 1at a hydrolysis temperature of 40° C. The residue obtained afterevaporation of the EA extracts was purified by RP HPLC (water/ACNgradient) to yield the title compound.

¹H-NMR: δ=12.1 (s, 1H); 8.68 (d, 1H); 8.32 (s, 1H); 8.24 (d, 1H); 8.09(s, 1H); 7.96 (d, 1H); 7.88 (d, 1H); 7.69 (t, 1H); 3.95 (s, 3H);2.15-2.04 (m, 4H); 1.60-1.45 (m, 8H)

In analogy to example 92, the example compounds of the formula I-4listed in table 4 were prepared by using the respective substitutedphenylboronic acid instead of 3-cyano-phenylboronic acid. The compoundsof the formula I-4 listed in table 4 can be named as1-[(5-R¹⁰⁴-6-methoxy-pyridine-3-carbonyl)-amino]-cycloheptanecarboxylicacid, for example as1-{[5-(3-chloro-phenyl)-6-methoxy-pyridyl-3-carbonyl]-amino}-cycloheptanecarboxylicacid in the case of example 94.

TABLE 4 Example compounds of the formula I-4 Reten- tion Exam- LC/MStime ple R¹⁰⁴ Method m/z [min] 93 3-dimethylaminosulfonylamino- LC9491.17 2.99 phenyl [MH⁺] 94 3-chloro-phenyl LC9 403.16 3.44 [MH⁺] 953-isopropyl-phenyl LC5 409.22 5.04 [M − H]⁻ 96 3-trifluoromethoxy-phenylLC4 453.22 1.34 [MH⁺] 97 2,3-dichloro-phenyl LC4 437.16 1.32 [MH⁺] 983,4,5-trifluoro-phenyl LC4 423.2  1.33 [MH⁺] 993-chloro-5-trifluoromethyl- LC4 471.2  1.39 phenyl [MH⁺] 1003-trifluoromethyl-phenyl LC4 437.23 1.34 [MH⁺]

EXAMPLE 1011-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

The compound can be prepared in analogy to example 92.

EXAMPLE 1021-{[5-(2-Fluoro-3-trifluoromethyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylicacid

The compound can be prepared in analogy to example 92.

In analogy to example 92, the example compounds of the formula I-5listed in table 5 were prepared by synthesizing the intermediate1-(3-bromo-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methylester in analogy to step 2 of example 92 using 3-bromo-4-methoxybenzoicacid instead of 5-bromo-6-methoxy-nicotinic acid. The intermediate wastransformed into the example compounds in analogy to example 92, steps 3and 4, using the appropriate phenylboronic acid. The compounds can benamed as 1-[(substitutedbiphenyl-3-carbonyl)-amino]-cycloheptanecarboxylic acid, for example as1-[(3′-cyano-6-methoxy-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylicacid in the case of example 104 in which the group R¹⁰⁵ is3-chloro-phenyl and the group 3-(R¹⁰⁵)-4-methoxy-phenyl-C(O) depicted informula I-5 thus is the group 3′-cyano-6-methoxy-biphenyl-3-carbonyl.

TABLE 5 Example compounds of the formula I-5 Reten- tion Exam- LC/MS m/ztime ple R¹⁰⁵ Method [MH⁺] [min] 103 3-dimethylaminosulfonylamino- LC10490.27 3.29 phenyl 104 3-chloro-phenyl LC9 402.14 3.49 1053-isopropyl-phenyl LC10 410.29 3.93 106 3-cyano-phenyl LC9 393.17 3.28

EXAMPLE 1071-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cycloheptanecarboxylicacid

Step 1: 3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoic acid

2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol and 3-hydroxy-4-methoxybenzoicacid methyl ester were coupled in analogy to step 1 of example 1 and themethyl ester was hydrolyzed in analogy to step 2 of example 1 to yieldthe title compound.

LC/MS (Method LC9): Rt=2.69 min; m/z=317.18 [MH⁺]

Step 2:1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cycloheptanecarboxylicacid methyl ester

The compound of step 1 (280 mg, 0.885 mmol) was dissolved in DMF (1.3ml) and HOBT (24 mg), 1-amino-cycloheptanecarboxylic acid methyl esterhydrochloride (221 mg, 1.06 mmol) and EDIA (578 mg, 4.43 mmol) wereadded. The mixture was cooled in an ice bath and EDC (254 mg, 1.33 mmol)was added. The mixture was stirred at room temperature for 3 days andpartitioned between EA and water. The aqueous phase was extracted withEA, the combined organic phases were dried over sodium sulfate andevaporated to dryness. The residue was purified by RP HPLC (water/ACNgradient) to yield the title compound (120 mg).

LC/MS (Method LC9): Rt=3.29 min; m/z=470. [MH⁺]

Step 3:1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cycloheptanecarboxylicacid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1to yield the title compound (89 mg).

¹H-NMR: δ=12.0 (s, 1H); 8.07 (s, 1H); 7.50 (dd, 1H); 7.40 (s, 1H);7.23-7.18 (m, 2H); 7.15 (d, 1H); 7.06 (d, 1H); 7.01 (d, 1H); 4.61 (t,1H); 4.21 (t, 2H); 3.80 (s, 3H); 3.59 (dt, 2H); 3.02 (t, 2H); 2.70 (t,2H); 2.12-2.02 (m, 4H); 1.57-1.42 (m, 8H)

EXAMPLE 1081-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cyclooctanecarboxylicacid

The title compound was synthesized in analogy to example 107 using1-amino-cyclooctanecarboxylic acid methyl ester hydrochloride instead of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): Rt=3.21 min; m/z=470.25 [MH⁺]

EXAMPLE 109cis-1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 107 usingcis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.21 min; m/z=456.34 [MH⁺]

EXAMPLE 110trans-1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 107 usingtrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.21 min; m/z=456.33 [MH⁺]

EXAMPLE 111cis-4-Ethyl-1-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 107 usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.25 min; m/z=470.36 [MH⁺]

EXAMPLE 112trans-4-Ethyl-1-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 107 usingtrans-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC3): Rt=4.30 min; m/z=470.36 [MH⁺]

EXAMPLE 113cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamio]-4-methyl-cyclohexanecarboxylicacid

Step 1: 3-Acetoxy-4-hydroxy-benzoic acid ethyl ester

3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolvedin DMF (5 ml), potassium tert-butylate (210 mg, 2.87 mmol) was added andthe mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) wasadded and stirring continued for 10 min. The mixture was partitionedbetween EA and 2 N hydrochloric acid, the aqueous phase extracted withEA, the combined organic phases were dried over sodium chloride,decanted and evaporated to dryness. The residue was purified by RP HPLC(water/ACN gradient) to yield the title compound.

¹H-NMR: δ=10.6 (s, 1H); 7.71 (dd, 1H); 7.58 (d, 1H); 7.00 (d, 1H); 4.25(q, 2H); 2.27 (s, 3H); 1.29 (t, 3H)

Step 2: 3-Acetoxy-4-benzyloxy-benzoic acid ethyl ester

The compound of step 1 (20 g, 89.2 mmol) was dissolved in DMF (100 ml)and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and,immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added.This mixture was stirred for 30 min at room temperature, poured on amixture of 2 N hydrochloric acid and diethyl ether, filtered and washedrepeatedly with diethyl ether. The combined ethereal phases were washedwith water, dried over sodium chloride, decanted and evaporated todryness. The residue was purified by silica gel chromatography (HEP/EAgradient) to yield the title compound (21 g).

¹H-NMR: δ=7.82 (dd, 1H); 7.67 (d, 1H); 7.43-7.37 (m, 5H); 7.30 (d, 1H);5.24 (s, 2H); 4.27 (q, 2H); 2.26 (s, 3H); 1.30 (t, 3H)

Step 3: 4-Benzyloxy-3-hydroxy-benzoic acid ethyl ester

The compound of step 2 (10 g, 31.8 mmol) was dissolved in methanol,potassium carbonate (88 mg, 0.636 mmol) was added and the mixture wasstirred for 2 h under reflux. The solution was evaporated to dryness andthe residue used without further purification.

¹H-NMR: δ=9.7 (br s, 1H); 7.48 (d, 2H); 7.42-7.30 (m, 5H); 7.06 (d, 1H);5.19 (s, 2H); 4.22 (q, 2H); 1.28 (t, 3H)

Step 4: 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoic acid ethylester

The compound of step 3 was coupled to 2-(3-chloro-phenyl)-ethanol inanalogy to step 1 of example 1 to yield the title compound.

¹H-NMR: δ=7.57 (dd, 1H); 7.49-7.24 (m, 10H); 7.17 (d, 1H); 5.17 (s, 2H),4.31-4.21 (m. 4H); 3.06 (t, 2H); 1.29 (t, 3H)

Step 5: 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoic acid

The compound of step 4 was hydrolyzed in analogy to step 2 of example 1to yield the title compound.

¹H-NMR: δ=12.7 (s, 1H); 7.53 (dd, 1H); 7.48-7.26 (m, 9H); 7.12 (d, 1H);5.17 (s, 2H); 4.26 (t, 2H); 3.07 (t, 2H)

Step 6:cis-1-{4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoylamino}-4-methyl-cyclohexanecarboxylicacid methyl ester

The compound of step 5 was coupled tocis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 2 of example 64 to yield the titlecompound.

¹H-NMR: δ=8.12 (s, 1H); 7.49-7.25 (m, 11H); 7.08 (d, 1H); 5.12 (s, 2H);4.28 (t, 2H); 3.55 (s, 3H); 3.08 (t, 2H); 2.22 (d, 2H); 1.69-1.59 (m,2H); 1.53-1.44 (m, 2H); 1.41-1.30 (m, 1H); 1.24-1.12 (m, 2H); 0.87 (d,3H)

Step 7:cis-1-{3-[2-(3-Chloro-phenyl)-ethoxy]-4-hydroxy-benzoylamino}-4-methyl-cyclohexanecarboxylicacid methyl ester

The compound of step 6 (410 mg, 0.765 mmol) was dissolved in methanol (3ml), cooled in an acetone/dry ice bath, and acetyl chloride (2.7 ml,38.2 mmol) was added with stirring. This mixture was stirred for 72 h atroom temperature and evaporated to dryness.

¹H-NMR: δ=9.58 (s, 1H); 8.01 (s, 1H); 7.49-7.27 (m, 6H); 6.82 (d, 1H);4.22 (t, 2H); 3.55 (s, 3H); 3.08 (t, 2H); 2.26-2.19 (m, 2H); 1.68-1.59(m, 2H); 1.52-1.48 (m, 2H); 1.42-1.32 (m, 1H); 1.23-1.12 (m, 2H); 0.85(d, 3H)

Step 8:cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid methyl ester

The compound of step 7 (150 mg, 0.337 mmol) was dissolved in DMF (7 ml),and potassium carbonate (233 mg, 1.68 mmol) and 2-bromoethyl methylether (70 mg, 0.51 mmol) were added subsequently. The mixture wasstirred for 48 h and then partitioned between water and EA. The aqueousphase was extracted with EA, the combined organic phases were dried oversodium sulfate and evaporated to dryness to yield the title compound(145 mg).

¹H-NMR: δ=8.11 (s, 1H); 7.48-7.26 (m, 6H); 7.02 (d, 1H); 4.29-4.20 (m,2H); 4.13 (t, 2H); 3.69 (t, 2H); 3.56 (s, 3H); 3.30 (s, 3H); 3.08 (t,2H); 2.27-2.20 (m, 2H); 1.69-1.61 (m, 2H); 1.53-1.49 (m, 2H); 1.42-1.33(m, 1H); 1.25-1.15 (m, 2H); 0.88 (d, 3H)

Step 9:cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamio]-4-methyl-cyclohexanecarboxylicacid

The compound of step 8 was hydrolyzed on analogy to step 4 of example 1.

¹H-NMR: δ=12.1 (br s, 1H); 7.98 (s, 1H); 7.49-7.38 (m, 3H); 7.37-7.21(m, 3H); 7.02 (d, 1H); 4.23 (t, 2H); 4.11 (t, 2H); 3.68 (t, 2H); 3.32(s, 3H); 3.08 (t, 2H); 2.28 (d, 2H); 1.68-1.59 (m, 2H); 1.51 (d, 2H);1.42-1.32 (m, 1H); 1.24-1.12 (m, 2H); 0.86 (d, 3H)

In analogy to example 113, the compounds of examples 114 and 115 weresynthesized using the respective amino acid methyl ester hydrochloridein the amide coupling step 6.

EXAMPLE 114trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.09 (s, 1H); 7.48-7.38 (m, 3H); 7.36-7.24 (m,3H); 7.01 (d, 1H); 4.21 (t, 2H); 4.11 (dd, 2H); 3.68 (dd, 2H); 3.32 (s,3H); 3.07 (t, 2H); 2.30-2.22 (m, 2H); 1.65-1.51 (m, 4H); 1.50-1.38 (m,1H); 1.32-1.19 (m, 2H); 0.89 (d, 3H)

EXAMPLE 1151-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

¹H-NMR: δ=11.98 (s, 1H); 8.07 (s, 1H); 7.50-7.42 (m, 2H); 7.41 (s, 1H);7.38-7.25 (m, 3H); 7.01 (d, 1H); 4.22 (t, 2H); 4.11 (dd, 2H); 3.69 (dd,2H); 3.30 (s, 3H); 3.07 (t, 2H); 2.12-2.02 (m, 4H); 1.60-1-42 (m, 8H)

In analogy to example 113, the compounds of examples 116 to 118 weresynthesized using the respective alcohol in the etherification step 4and the respective amino acid methyl ester hydrochloride in the amidecoupling step 6. In step 7, cleavage of the benzyl ether wasaccomplished by dissolution of the starting material in methanol,addition of palladium on charcoal (10%), hydrogenation under 1 barhydrogen pressure for 1 h, filtration and evaporation to dryness.

EXAMPLE 1161-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylicacid

¹H-NMR: δ=11.9 (s, 1H); 8.07 (s, 1H); 7.46 (dd, 1H); 7.41 (s, 1H);7.19-7.11 (m, 3H); 7.02 (t, 2H); 4.19 (t, 2H); 4.11 (t, 2H); 3.68 (t,2H); 3.31 (s, 3H); 3.00 (t, 2H); 2.29 (s, 3H); 2.10-2.00 (m, 4H);1.58-1.42 (m, 8H)

EXAMPLE 117trans-1-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexane-carboxylicacid

¹H-NMR: δ=12.00 (s, 1H); 8.08 (s, 1H); 7.44 (dd, 1H); 7.40 (d, 1H);7.20-7.11 (m, 3H); 7.01 (d, 1H); 6.99 (d, 1H); 4.20 (t, 2H); 4.11 (ddd,2H); 3.68 (ddd, 2H); 3.30 (s, 3H); 3.00 (t, 2H); 2.30 (s, 3H); 2.30-2.23(m, 2H); 1.62-1.52 (m, 4H); 1.50-1.41 (m, 1H); 1.31-1.20 (m, 2H); 0.89(d, 3H)

EXAMPLE 118cis-1-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexane-carboxylicacid

¹H-NMR: δ=12.1 (s, 1H); 7.99 (s, 1H); 7.46 (dd, 1H); 7.41 (s, 1H);7.20-7.11 (m, 3H); 7.02 (d, 2H); 4.21 (t, 2H); 4.11 (ddd, 2H); 3.68(ddd, 2H); 3.30 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.27-2.22 (m, 2H);1.69-1.59 (m, 2H); 1.53-1.47 (m, 2H); 1.42-1.31 (m, 1H); 1.22-1.12 (m,2H); 0.87 (d, 3H)

EXAMPLE 119cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

The title compound of step 7 of example 113 (150 mg, 0.337 mmol) wasreacted in analogy to step 8 of example 113 using 2-bromoethyl acetateas alkylating agent, followed by hydrolysis in analogy to step 4 ofexample 1 to yield the title compound.

¹H-NMR: δ=12.1 (s, 1H); 7.97 (s, 1H); 7.51-7.27 (m, 6H); 7.03 (d, 1H);4.85 (t, 1H); 4.25 (t, 2H); 4.07-3.99 (m, 2H); 3.78-3.70 (m, 2H); 3.08(t, 2H); 2.28 (d, 2H); 1.70-1.57 (m, 2H); 1.53-1.42 (m, 2H); 1.42-1.31(m, 1H); 1.23-1.11 (m, 2H); 0.88 (d, 3H)

In analogy to example 119, the compounds of examples 120 and 121 weresynthesized using the respective amino acid methyl ester hydrochloridein the amide coupling step.

EXAMPLE 120trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.08 (s, 1H); 7.49-7.26 (m, 6H); 7.02 (d, 1H);4.82 (t, 1H); 4.22 (t, 2H); 4.02 (t, 2H); 3.80-3.70 (m, 2H); 3.08 (t,2H); 2.29 (d, 2H); 1.63-1.40 (m, 4H); 1.32-1.18 (m, 3H); 0.88 (d, 3H)

EXAMPLE 1211-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-cycloheptane-carboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.08 (s, 1H); 7.50-7.25 (m, 6H); 7.02 (d, 1H);4.82 (t, 1H); 4.22 (t, 2H); 4.01 (t, 2H); 3.78-3.70 (m, 2H); 3.09 (t,2H); 2.12-2.02 (m, 4H); 1.58-1.42 (m, 8H)

In analogy to example 119, the compounds of examples 122 to 124 weresynthesized using 2-m-tolyl-ethanol in the ether coupling step 4 ofexample 113 and the respective amino acid methyl ester hydrochloride inthe amide coupling step 6. In step 7, cleavage of the benzyl ether wasaccomplished by dissolution of the starting material in methanol,addition of palladium on charcoal (10%), hydrogenation under 1 barhydrogen pressure for 1 h, filtration and evaporation to dryness.

EXAMPLE 122trans-1-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.08 (s, 1H); 7.46-7.38 (m, 2H); 7.20-7.11 (m,3H); 7.03-6.99 (m, 2H); 4.84 (t, 1H); 4.19 (t, 2H); 4.01 (t, 2H); 3.72(dt, 2H); 3.00 (t. 2H); 2.30 (s, 3H); 2.29-2.21 (m, 2H); 1.61-1.51 (m,4H); 1.51-1.39 (m, 1H); 1.30-1.18 (m, 2H); 0.88 (d, 3H)

EXAMPLE 123cis-1-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.1 (s, 1H); 7.97 (s, 1H); 7.48 (dd, 1H); 7.39 (d, 1H);7.19-7.11 (m, 3H); 7.02 (d, 2H); 4.82 (t, 1H); 4.21 (t, 2H); 4.02 (t,2H); 3.72 (dt, 2H); 3.01 (t, 2H); 2.29 (s, 3H); 2.29-2.22 (m, 2H);1.68-1.59 (m, 2H); 1.51-1.44 (m, 2H); 1.41-1.31 (m, 1H); 1.21-1.11 (m,2H); 0.88 (d, 3H)

EXAMPLE 1241-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptane-carboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.08 (s, 1H); 7.47 (dd, 1H); 7.60 (d, 1H);7.21-7.12 (m, 3H); 7.05-7.00 (m, 2H); 4.82 (t, 1H); 4.20 (t, 1H); 4.01(t, 2H); 3.72 (dt, 2H); 2.99 (t, 2H); 2.29 (s, 3H); 2.11-2.00 (m, 4H);1.57-1.42 (m, 8H)

EXAMPLE 125cis-1-[(3′-Chloro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylicacid

Step 1: 3′-Chloro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carboxylicacid

3-Bromo-4-trifluoromethyl-benzoic acid (0.484 g, 1.80 mmol),3-chloro-4-methoxy-phenylboronic acid (0.503 g, 2.70 mmol),tri-tert-butylphosphonium tetrafluoroborate (0.313 g, 1.08 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) andpotassium fluoride (0.345 g, 5.93 mmol) were weighed into a flask anddioxane (10 ml) was added under argon, and the mixture was stirred for24 h at 50° C. The mixture was filtered over celite and evaporated todryness. The residue was purified by preparative RP HPLC (water/ACNgradient) to yield the title compound.

Step 2:cis-1-[(3′-Chloro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylicacid

The compound of step 1 was coupled withcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3 and hydrolyzed inanalogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt=1.39 min; m/z=484.31 [MH⁺]

EXAMPLE 126(1R,2S,4S)-2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid and(1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid

Step 1: Spiro[imidazolidine-2,4-dione-5,2′-7-oxabicyclo[2.2.1]heptane]

27.6 g of ammonium carbonate were dissolved in 200 ml of water and 200ml of ethanol. 12.4 g of 7-oxa-bicyclo[2.2.1]heptan-2-one (A. Warm etal., Helv. Chim. Acta 70 (1987), 690-700) were added and the mixture wasstirred at 50° C. for 4 h. Then a solution of 7.2 g of potassium cyanidein 55 ml of water and 55 ml of ethanol was added and the mixture stirredat 50° C. for 16 h. Afterwards the mixture was concentrated to a volumeof about 100 ml, 3 g of sodium chloride were added and the mixture wasstirred at room temperature for 2 h. The precipitate was filtered off,washed with water and dried to yield 10.4 g of the title compound as aracemic mixture.

Step 2: 2-Amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid

9.0 g of spiro[imidazolidine-2,4-dione-5,2′-7-oxabicyclo[2.2.1]heptane]and 77.9 g of barium hydroxide octahydrate were dissolved in 135 ml ofwater, divided into 9 portions and treated under microwave irradiationat 190° C. for 30 min. The pooled mixture were diluted with 300 ml ofwater, heated to 90° C. and the precipitate was filtered off by suction.Then 4.5 g of ammonium carbonate were added to the filtrate and themixture was heated to 90° C. 50 g of solid carbon dioxide were thenadded and the mixture was stirred at 90° C. for 10 min. The precipitatedbarium carbonate was filtered off by suction. Then another 50 g of solidcarbon dioxide were added to the filtrate and the mixture was stirred at50° C. for 1 h. The precipitated barium carbonate was filtered off bysuction. The filtrate was evaporated in vacuo to yield 6.3 g of thetitle compound as a racemic mixture.

Step 3: 2-Amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methylester

3.0 g of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid weresuspended in 100 ml of methanol and 11.4 g of thionyl chloride wereadded at room temperature. The mixture was left at room temperature for24 h. Then the volatiles were evaporated in vacuo to yield 3.9 g of thetitle compound as a racemic mixture.

LC/MS (Method LC6): Rt=0.53 min; m/z=172.21 [MH⁺]

Step 4:2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid methyl ester)

550 mg of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), 300 mg of2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester and410 mg of 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid (example 2) werestirred in 20 ml of anhydrous DMF for 15 h at room temperature. Themixture was diluted with 150 ml of EA and washed three times with 50 mleach of a saturated aqueous sodium carbonate solution and then threetimes with 50 ml each of a 10% aqueous sodium hydrogensulfate solution.The organic layer was dried with magnesium sulfate, evaporated todryness and the residue purified by silica gel chromatography (HEP/EAgradient) to yield 630 mg of the title compound as a racemic mixture.

LC/MS (Method LC4): Rt=1.22 min; m/z=440.34 [MH⁺]

Step 5:(1R,2S,4S)-2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid and(1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid

630 mg of2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid methyl ester was dissolved in 10 ml of methanol, and 2.2 ml of a 1N solution of sodium hydroxide in water were added at room temperature.The mixture was stirred at 40° C. for 5 h, then another 1.1 ml of a 1 Nsolution of sodium hydroxide in water were added and the mixture stirredat 40° C. for another 4 h. The mixture was then diluted with 40 ml ofwater, the methanol was evaporated, the pH adjusted to 2 and the mixturestirred at room temperature of 1 h. The precipitated product wasfiltered off and dried in vacuo to yield 400 mg of2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid as a racemic mixture of(1R,2S,4S)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid and(1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylicacid.

LC/MS (Method LC3): Rt=4.00 min; m/z=426.18 [MH⁺]

EXAMPLE 127cis-4-Ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cyclohexanecarboxylicacid

Step 1: 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-phenylboronic acid

50.0 g of [2-(3-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane weredissolved in 500 ml of anhydrous THF. 64.6 ml of a 2.7 M solution ofn-butyllithium in n-heptane were added dropwise at −70° C. The mixturewas stirred for 1 h at −70° C. Then 40.2 ml of triisopropyl borate wereadded dropwise at −70° C. Stirring was continued for 30 min at −70° C.and the mixture allowed to warm up to −20° C. 500 ml of water were addedand the mixture was extracted three time with 500 ml each of DCM. Thecombined organic layers were dried with magnesium sulfate and evaporatedto yield 43.6 g of the title compound.

LC/MS (Method LC4): Rt=1.32 min; m/z=325.13 [M−H+HCOOH]⁻

Step 2: tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane

4.6 g of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenylboronicacid, 130 mg of nickel iodide, 5.0 g of sodium bis(trimethylsilyl)amideand 62 mg of (1R,2R)-2-amino-cyclohexanol were placed in a microwavevial and 3.5 ml of isopropanol were added. The mixture was stirred for10 min at room temperature. Then a solution of 3-iodooxetane in 1.5 mlof isopropanol was added and the mixture treated under microwaveirradiation at 80° C. for 30 min. The obtained mixture was combined withthe mixtures obtained in three further runs of the synthesis, pouredinto 50 ml of a saturated aqueous sodium hydrogencarbonate solution andextracted three time with 50 ml each of EA. The combined organic layerswere dried with magnesium sulfate and evaporated to yield 9.0 g of thetitle compound.

Step 3: 2-(3-Oxetan-3-yl-phenyl)-ethanol

9.0 g of tert-butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silaneand 92.3 ml of a 1 N solution of tetra-n-butylammonium fluoride weredissolved in 200 ml of anhydrous THF. The mixture was stirred for 3 h atroom temperature. Then the mixture was poured into 200 ml of a saturatedaqueous solution of sodium hydrogencarbonate and extracted three timeswith 500 ml each of EA The combined organic layers were dried withmagnesium sulfate and evaporated. The residue was purified by silica gelchromatography (HEP/EA gradient) to yield 4.9 g of the title compound.

Step 4: Toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester

4.9 g of 2-(3-oxetan-3-yl-phenyl)-ethanol were dissolved in 30 ml of DCMand 9.5 ml of pyridine were added at room temperature. The mixture wascooled to 0° C. and 6.3 g of p-toluenesulfonyl chloride were added at 0°C. Stirring was continued for 6 h at room temperature. Then thevolatiles were evaporated, the residue was dissolved in 100 ml of EA andwashed with 100 ml of a saturated aqueous solution of sodiumhydrogencarbonate. The aqueous layer was extracted two times with 100 mleach of EA. The combined organic layers were dried with magnesiumsulfate and evaporated. Silica gel chromatography (EA/HEP 1:1) of theresidue yielded 2.0 g of the title compound.

LC/MS (Method LC4): Rt=1.26 min; m/z=333.16 [MH]⁺

Step 5: 3-Acetoxy-4-methoxy-benzoic acid

17.0 g of 3-hydroxy-4-methoxy-benzoic acid and 51.6 g of aceticanhydride were combined and stirred at 140° C. for 3 h. Then 50 ml ofwater were added at 100° C., the mixture was heated under reflux for 30min, another 200 ml of water were added and the mixture heated underreflux for 30 min. The mixture was cooled to 0° C., and the product wasfiltered off, washed with water and dried in vacuo to yield 18.8 g ofthe title compound.

LC/MS (Method LC4): Rt=0.93 min; m/z=209.14 [M−H]⁻

Step 6: Acetic acid 5-chlorocarbonyl-2-methoxy-phenyl ester

700 mg of 3-acetoxy-4-methoxy-benzoic acid were suspended in 6 ml ofanhydrous DCM and 24 μl of DMF were added. Then 5.0 ml of a 2 M solutionof oxalyl chloride in DCM were added dropwise. The mixture was stirreduntil the evolution of gas had ceased (about 30 min). The volatiles wereremoved in vacuo, the residue was dissolved in 10 ml of DCM andevaporated to yield 750 mg of the title compound which was used in thesubsequent step without further purification.

Step 7:cis-1-(3-Acetoxy-4-methoxy-benzoylamino)-4-ethyl-cyclohexanecarboxylicacid methyl ester

100 mg of 1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester(prepared in analogy to example 25) were dissolved in 5 ml of EA and 10ml of a saturated aqueous solution of sodium hydrogencarbonate wereadded. A solution of 103 mg of acetic acid5-chlorocarbonyl-2-methoxy-phenyl ester in 3 ml of DCM was addeddropwise at 0° C. over a period of 5 min. Stirring was continued for 1 hat room temperature. The phases were allowed to separate. The aqueouslayer was extracted two times with 15 ml each of EA. The combinedorganic layers were dried with magnesium sulfate and evaporated to yield109 mg of the title compound.

Step 8:cis-4-Ethyl-1-(3-hydroxy-4-methoxy-benzoylamino)-cyclohexanecarboxylicacid methyl ester

109 mg of1-(3-acetoxy-4-methoxy-benzoylamino)-4-ethyl-cyclohexanecarboxylic acidmethyl ester were dissolved in 5 ml of methanol and 8.0 mg of potassiumcarbonate were added. The mixture was stirred at room temperature for 1h, then poured into 10 ml of 1 N hydrochloric acid and extracted threetimes with 10 ml of EA. The combined organic layers were washed twotimes with 10 ml each of a saturated aqueous solution of sodiumhydrogencarbonate, once with 10 ml of 1 N hydrochloric acid and oncewith 10 ml of a saturated aqueous solution of sodium chloride. Theorganic layer was dried with magnesium sulfate and evaporated. Silicagel chromatography (EA/HEP 1:1) of the residue yielded 18 mg of thetitle compound.

LC/MS (Method LC4): Rt=1.21 min; m/z=336.22 [MH⁺]

Step 9:cis-4-Ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cyclohexanecarboxylicacid methyl ester

17.8 mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester,18.0 mg of4-ethyl-1-(3-hydroxy-4-methoxy-benzoylamino)-cyclohexanecarboxylic acidmethyl ester and 22.3 mg of potassium carbonate were stirred in 1 ml ofDMF for 6 h at 40° C. Then 9.0 mg of toluene-4-sulfonic acid2-(3-oxetan-3-yl-phenyl)-ethyl ester were added and the mixture wasstirred for 5 h at 40° C. The reaction mixture was then diluted with 10ml of EA and washed with 10 ml of a saturated aqueous solution of sodiumchloride. The aqueous layer was extracted two times with 10 ml of EA.The combined organic layers were dried with magnesium sulfate, andevaporated. Silica gel chromatography (EA/HEP, 1:1) of the residueyielded 20 mg of the title compound.

LC/MS (Method LC4): Rt=1.34 min; m/z=496.29 [MH⁺]

Step 10:cis-4-Ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cyclohexanecarboxylicacid

20 mg of4-ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cyclohexanecarboxylicacid methyl ester were dissolved in 1 ml of methanol and 48 μl of a 1 Maqueous solution of sodium hydroxide were added. The mixture was stirredfor 7 h at 60° C. and then poured into 10 ml of water. The pH wasadjusted to 5 with a 5% aqueous solution of sodium hydrogensulfate. Themixture was extracted three time with 15 ml each of EA. The combinedorganic layers were dried with magnesium sulfate and evaporated to yield14 mg of the title compound.

LC/MS (Method LC4): Rt=1.28 min; m/z=480.38 [M−H]

EXAMPLE 128trans-1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 127.

LC/MS (Method LC4): Rt=1.24 min; m/z=466.2 [M−H]⁻

EXAMPLE 1291-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 127.

LC/MS (Method LC4): Rt=1.23 min; m/z=466.37 [M−H]⁻

EXAMPLE 130cis-4-Ethyl-1-[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

Step 1: 4-Iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

10.0 g of 3-hydroxy-4-iodo-benzoic acid methyl ester, 7.2 g of1-(2-bromo-ethyl)-3-methyl-benzene and 10.0 g of potassium carbonatewere stirred in 100 ml of anhydrous DMF for 28 h at 80° C. The solventwas evaporated and the residue dissolved in 200 ml of water and 400 mlof EA. The organic layer was separated, washed with 200 ml of water,dried with magnesium sulfate and evaporated. Silica gel chromatography(EA/HEP gradient) of the residue yielded 4.66 g of the title compound.

Step 2: 4-Borono-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

2.3 g of bis(2-dimethylaminoethyl)ether were dissolved in 50 ml ofanhydrous THF and 7.1 ml of a 2 M solution of isopropylmagnesiumchloride added at 15° C. The mixture was stirred for 20 min at 15° C.Then a solution of 4.7 g of 4-iodo-3-(2-m-tolyl-ethoxy)-benzoic acidmethyl ester in 20 ml of anhydrous THF was added at room temperature.The mixture was stirred for 10 min at 20° C., and then 2.4 g oftrimethyl borate were added dropwise at 0° C. and the mixture stirredfor 20 min at 0° C. 100 ml of 0.1 N hydrochloric acid were added, andthe mixture was extracted three times with 100 ml of EA. The combinedorganic layers were washed with 100 ml of water, dried with magnesiumsulfate and evaporated. Silica gel chromatography (EA/HEP 1:5) of theresidue yielded 2.1 g of the title compound.

TLC (silica gel, EA/HEP 1:5): Rf=0.16

Step 3: 4-Oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid isopropyl ester

2.0 g of 4-borono-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester, 51 mgof nickel iodide, 2.0 g of sodium bis(trimethylsilyl)amide and 25 mg oftrans-2-aminocyclohexanol hydrochloride were placed into a microwavevial and 10 ml of anhydrous 2-propanol added. The mixture was stirredfor 10 min. Then a solution of 1.0 g of 3-iodo-oxetane in 3 ml ofanhydrous 2-propanol was added and the mixture reacted for 40 min at 80°C. under microwave irradiation. The mixture was then poured into 150 mlof EA and washed three times with 30 ml each of a saturated aqueoussodium hydrogensulfate solution and three times with 30 ml each of asaturated aqueous sodium carbonate solution. The organic layer was driedwith magnesium sulfate and evaporated. Silica gel chromatography (EA/HEP1:5) of the residue yielded 120 mg of the title compound.

TLC (silica gel, EA/HEP 1:5): Rf=0.20

Step 4: 4-Oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid

120 mg of 4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid isopropylester were dissolved in 3 ml of methanol and 0.2 ml of a 2 N aqueoussolution of sodium hydroxide added. The mixture was left at roomtemperature for 6 days and then evaporated. The residue was dissolved in10 ml of water, the pH adjusted to 2 with an aqueous sodiumhydrogensulfate solution, and the mixture extracted three times using 20ml each of DCM. The combined extracts were dried with magnesium sulfateand evaporated to yield 105 mg of the title compound.

Step 5:cis-4-Ethyl-1-[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

cis-4-Ethyl-1-[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid methyl ester was synthesized from4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid andcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to example 126, step 4, and the esterhydrolyzed to the title compound in analogy to example 126, step 5.

LC/MS (Method LC4): Rt=1.36 min; m/z=466.33 [MH⁺]

EXAMPLE 131cis-1-[4-Oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 130.

LC/MS (Method LC4): Rt=1.31 min; m/z=504.44 [M−H]⁻

EXAMPLE 1321-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylicacid

Step 1: 7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid2-m-tolyl-ethyl ester

2.5 g of 7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid, 6.8 g of1-(2-bromo-ethyl)-3-methyl-benzene and 7.6 g of potassium carbonate werestirred in 100 ml of anhydrous DMF for 10 h at 80° C. Then another 1.4 gof 1-(2-bromo-ethyl)-3-methyl-benzene and 1.5 g of potassium carbonatewere added and the mixture was stirred for 5 h at 90° C. The solvent wasremoved in vacuo and the residue dissolved in 200 ml of water and 200 mlof EA. The organic layer was separated, washed with 100 ml of asaturated aqueous sodium carbonate solution, dried with magnesiumsulfate and evaporated to yield 4.5 g of the title compound.

Step 2: 7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid

4.5 g of 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid2-m-tolyl-ethyl ester and 650 mg of sodium hydroxide were dissolved in50 ml of methanol, 50 ml of THF and 5 ml of water. The mixture was keptat room temperature for 20 h, then stirred at 50° C. for 5 h andevaporated. The residue was dissolved in 300 ml of a 0.1 M aqueoussolution of sodium hydroxide and washed three times with 50 ml each ofdiisopropyl ether. The pH was adjusted to 2 with sodium hydrogensulfateand the mixture stirred for 30 min at room temperature. The product wascollected by filtration, washed and dried in vacuo to yield 3.1 g of thetitle compound.

LC/MS (Method LC4): Rt=1.23 min; m/z=299.16 [M−H]⁻

Step 3:1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylicacid methyl ester

The title compound was synthesized from7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid and1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride inanalogy to example 126, step 4.

LC/MS (Method LC4): Rt=1.4 min; m/z=454.31 [MH⁺]

Step 4:1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylicacid

The title compound was synthesized from1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylicacid methyl ester in analogy to example 126, step 5.

LC/MS (Method LC4): Rt=1.33 min; m/z=440.24 [MH⁺]

EXAMPLE 133cis-1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 132.

LC/MS (Method LC4): Rt=1.33 min; m/z=494.25 [MH⁺]

EXAMPLE 134cis-4-Ethyl-1-{[7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 132.

LC/MS (Method LC4): Rt=1.37 min; m/z=454.29 [MH⁺]

In analogy to example 3, the example compounds of the formula I-6 listedin table 6 were prepared. The compounds can be named ascis-1-[3-(R¹⁰⁶-oxy)-4-methoxy-benzoylamino]-4-methyl-cyclohexane-1-carboxylicacid, for example ascis-1-{3-[2-(4-methoxy-phenyl)-ethoxy]-4-methoxy-benzoylamino]-4-methyl-cyclohexane-1-carboxylicacid in the case of example 135.

TABLE 6 Example compounds of the formula I-6 Reten- tion Exam- LC/MS m/ztime ple R¹⁰⁶ Method [MH⁺] [min] 135 2-(4-methoxy-phenyl)-ethyl LC4442.32 1.29 136 2-cyclohexyl-ethyl LC4 418.35 1.39 1372-(3-trifluoromethyl-phenyl)-ethyl LC4 480.3 1.34 1382-(thiophen-2-yl)-ethyl LC4 418.26 1.28 139 2-(3-fluoro-phenyl)-ethylLC4 430.29 1.3 140 2-(3,4-dimethoxy-phenyl)-ethyl LC4 472.34 1.25 1412-(4-chloro-phenyl)-ethyl LC4 446.27 1.34 1422-(4-tert-butyl-phenyl)-ethyl LC4 468.37 1.4 143 2-phenyl-propyl LC4426.3 1.33 144 2-(2-trifluoromethyl-phenyl)-ethyl LC4 480.32 1.34 1452-(3-chloro-phenyl)-ethyl LC4 446.26 1.34 146 2-(4-cyano-phenyl)-ethylLC4 437.3 1.26 147 2-(thiophen-3-yl)-ethyl LC4 418.27 1.28 1482-(2,4-dichloro-phenyl)-ethyl LC4 480.24 1.38 1492-(2-chloro-4-fluoro-phenyl)-ethyl LC4 464.26 1.34 150[1-(4-chloro-phenyl)-cyclopropyl]- LC4 472.29 1.37 methyl 1512-(2-fluoro-phenyl)-ethyl LC4 430.29 1.3 1522-(2-chloro-6-fluoro-phenyl)-ethyl LC4 464.25 1.33 1532-(2-methyl-phenyl)-ethyl LC4 426.32 1.33 154 2-(4-fluoro-phenyl)-ethylLC4 430.29 1.3 155 2-(3-methoxy-phenyl)-ethyl LC4 442.31 1.29 1562-(2-chloro-phenyl)-ethyl LC4 446.25 1.33 1572-(2,5-dichloro-phenyl)-ethyl LC4 480.22 1.37

In analogy to example 3, the example compounds of the formula I-7 listedin table 7 were prepared. The compounds can be named astrans-1-[3-(R¹⁰⁷-oxy)-4-methoxy-benzoylamino]-4-methyl-cyclohexane-1-carboxylicacid, for example astrans-1-{3-[2-(4-methoxy-phenyl)-ethoxy]-4-methoxy-benzoylamino]-4-methyl-cyclohexane-1-carboxylicacid in the case of example 158.

TABLE 7 Example compounds of the formula I-7 Reten- tion Exam- LC/MS m/ztime ple R¹⁰⁷ Method [MH⁺] [min] 158 2-(4-methoxy-phenyl)-ethyl LC4442.3 1.28 159 2-cyclohexyl-ethyl LC4 418.35 1.38 1602-(3-trifluoromethyl-phenyl)-ethyl LC4 480.29 1.34 1612-(thiophen-2-yl)-ethyl LC4 418.24 1.28 162 2-(3-fluoro-phenyl)-ethylLC4 430.28 1.3 163 2-phenyl-ethyl LC4 412.29 1.29 1642-(2-methoxy-phenyl)-ethyl LC4 442.3 1.3 1652-(3,4-dimethoxy-phenyl)-ethyl LC4 470.47 1.25 1662-(4-chloro-phenyl)-ethyl LC4 446.26 1.33 1672-(4-tert-butyl-phenyl)-ethyl LC4 468.39 1.4 168 2-phenyl-propyl LC4426.33 1.32 169 2-(4-methyl-phenyl)-ethyl LC4 426.32 1.33 1702-(2-trifluoromethyl-phenyl)-ethyl LC4 480.29 1.34 1712-(3-chloro-phenyl)-ethyl LC4 446.27 1.33 172 2-(4-cyano-phenyl)-ethylLC4 437.3 1.25 173 2-(2,4,6-trimethyl-phenyl)-ethyl LC4 454.36 1.38 1742-(thiophen-3-yl)-ethyl LC4 418.26 1.28 1752-(2,4-dichloro-phenyl)-ethyl LC4 480.23 1.37 1762-(2-chloro-4-fluoro-phenyl)-ethyl LC4 464.27 1.33 1772-(2-fluoro-phenyl)-ethyl LC4 430.28 1.3 178 2-phenyl-butyl LC4 440.341.35 179 2-(2-chloro-6-fluoro-phenyl)-ethyl LC4 464.28 1.32 1802-(2-methyl-phenyl)-ethyl LC4 426.31 1.32 1812-(2,5-difluoro-phenyl)-ethyl LC4 448.28 1.3 1822-(3-chloro-2-fluoro-phenyl)-ethyl LC4 464.27 1.33 1832-(4-fluoro-phenyl)-ethyl LC4 430.29 1.29 184 2-(indol-3-yl)-ethyl LC4451.34 1.26 185 2-(3-methoxy-phenyl)-ethyl LC4 442.32 1.28 1862-(2-chloro-phenyl)-ethyl LC4 446.26 1.32 1872-(2,5-dimethyl-phenyl)-ethyl LC4 440.34 1.35 1882-(2,5-dichloro-phenyl)-ethyl LC4 480.24 1.36 1892-(3,5-dimethyl-phenyl)-ethyl LC4 440.33 1.36 1901-methyl-2-phenyl-ethyl LC4 426.31 1.31 191 4-methoxy-benzyl LC4 442.311.3 192 4-trifluoromethoxy-benzyl LC4 482.27 1.33 1933-(4-methoxy-phenyl)-propyl LC4 456.34 1.3 194 2-phenylsulfanyl-ethylLC4 444.27 1.3 195 3-chloro-benzyl LC4 432.25 1.31 1962-(naphthalen-1-yl)-ethyl LC4 462.33 1.35 197(2,3-dihydro-benzo[1,4]dioxin- LC4 456.31 1.29 2-yl)-methyl 1983-phenyl-propyl LC4 426.32 1.32 199 3-fluoro-benzyl LC4 416.28 1.28 200cyclohexyl-methyl LC4 404.32 1.36 201 3-cyclopentyl-propyl LC4 418.341.39 202 2,5-dimethyl-benzyl LC4 426.32 1.33 2032-(4-fluoro-phenylsulfanyl)-ethyl LC4 462.29 1.31 2042-(6,6-dimethyl-bicyclo[3.1.1]hept- LC4 456.39 1.43 2-en-2-yl)-ethyl

In analogy to example 3, the example compounds of the formulae I-8 and1-9 listed in table 8, in which R¹⁰⁸ and R¹⁰⁹ have the meanings given intable 8, were prepared.

TABLE 8 Example compounds of the formulae I-8 and I-9 Reten- tion Exam-For- LC/MS m/z time ple mula R¹⁰⁸/R¹⁰⁹ Method [MH⁺] [min] 205 I-82-phenyl-ethyl LC4 426.30 1.34 206 I-9 2-phenyl-ethyl LC4 426.29 1.22207 I-8 2-(3-chloro-phenyl)-ethyl LC4 460.27 1.38 208 I-92-(3-chloro-phenyl)-ethyl LC3 460.29 4.75

In analogy to example 3, the compounds of the formulae I-8 and 1-9listed in table 9, in which R¹⁰⁸ and R¹⁰⁹ have the meanings given intable 9, can be prepared.

TABLE 9 Compounds of the formulae I-8 and I-9 Example Example (formula)(formula) R¹⁰⁸/R¹⁰⁹ 209 (I-8) 210 (I-9) 2-(4-methoxy-phenyl)-ethyl 211(I-8) 212 (I-9) 2-cyclohexyl-ethyl 213 (I-8) 214 (I-9)2-(3-trifluoromethyl-phenyl)-ethyl 215 (I-8  216 (I-9)2-(thiophen-2-yl)-ethyl 217 (I-8) 218 (I-9) 2-(3-fluoro-phenyl)-ethyl219 (I-8) 220 (I-9) 2-(2-methoxy-phenyl)-ethyl 221 (I-8) 222 (I-9)2-(3,4-dimethoxy-phenyl)-ethyl 223 (I-8) 224 (I-9)2-(4-chloro-phenyl)-ethyl 225 (I-8) 226 (I-9)2-(4-tert-butyl-phenyl)-ethyl 227 (I-8) 228 (I-9) 2-phenyl-propyl 229(I-8) 230 (I-9) 2-(4-methyl-phenyl)-ethyl 231 (I-8) 232 (I-9)2-(2-trifluoromethyl-phenyl)-ethyl 233 (I-8) 234 (I-9)2-(4-cyano-phenyl)-ethyl 235 (I-8) 236 (I-9)2-(2,4,6-trimethyl-phenyl)-ethyl 237 (I-8) 238 (I-9)2-(thiophen-3-yl)-ethyl 239 (I-8) 240 (I-9)2-(2,4-dichloro-phenyl)-ethyl 241 (I-8) 242 (I-9)2-(2-chloro-4-fluoro-phenyl)-ethyl 243 (I-8) 244 (I-9)2-(2-fluoro-phenyl)-ethyl 245 (I-8) 246 (I-9) 2-phenyl-butyl 247 (I-8)248 (I-9) 2-(2-chloro-6-fluoro-phenyl)-ethyl 249 (I-8) 250 (I-9)2-(2-methyl-phenyl)-ethyl 251 (I-8) 252 (I-9)2-(2,5-difluoro-phenyl)-ethyl 253 (I-8) 254 (I-9)2-(3-chloro-2-fluoro-phenyl)-ethyl 255 (I-8) 256 (I-9)2-(4-fluoro-phenyl)-ethyl 257 (I-8) 258 (I-9) 2-(indol-3-yl)-ethyl 259(I-8) 260 (I-9) 2-(3-methoxy-phenyl)-ethyl 261 (I-8) 262 (I-9)2-(2-chloro-phenyl)-ethyl 263 (I-8) 264 (I-9)2-(2,5-dimethyl-phenyl)-ethyl 265 (I-8) 266 (I-9)2-(2,5-dichloro-phenyl)-ethyl 267 (I-8) 268 (I-9)2-(3,5-dimethyl-phenyl)-ethyl 269 (I-8) 270 (I-9)1-methyl-2-phenyl-ethyl 271 (I-8) 272 (I-9) 4-methoxy-benzyl 273 (I-8)274 (I-9) 4-trifluoromethoxy-benzyl 275 (I-8) 276 (I-9)3-(4-methoxy-phenyl)-propyl 277 (I-8) 278 (I-9) 2-phenylsulfanyl-ethyl279 (I-8) 280 (I-9) 3-chloro-benzyl 281 (I-8) 282 (I-9)2-(naphthalen-1-yl)-ethyl 283 (I-8) 284 (I-9)(2,3-dihydro-benzo[1,4]dioxin-2-yl)- methyl 285 (I-8) 286 (I-9)3-phenyl-propyl 287 (I-8) 288 (I-9) 3-fluoro-benzyl 289 (I-8) 290 (I-9)cyclohexyl-methyl 291 (I-8) 292 (I-9) 3-cyclopentyl-propyl 293 (I-8) 294(I-9) 2,5-dimethyl-benzyl 295 (I-8) 296 (I-9)2-(4-fluoro-phenylsulfanyl)-ethyl 297 (I-8) 298 (I-9)2-(6,6-dimethyl-bicyclo[3.1.1]hept-2- en-2-yl)-ethyl

In analogy to example 92, the example compounds of the formula I-10listed in table were synthesized by reactingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride with 5-bromo-6-methoxy-nicotinic acid in analogy tostep 2 of example 92, and reacting the obtainedcis-1-[(5-bromo-6-methoxy-pyridine-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylicacid methyl ester with the respective phenylboronic acid and hydrolyzingthe obtained methyl ester in analogy to steps 3 and 4, respectively, ofexample 92. The compounds can be named ascis-4-ethyl-1-[(5-R¹¹⁰-6-methoxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid, for example ascis-4-ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid in the case of example 299.

TABLE 10 Example compounds of the formula I-10 Reten- tion Exam- LC/MSm/z time ple R¹¹⁰ Method [MH⁺] [min] 299 3-trifluoromethoxy-phenyl LC4467.3 1.37 300 2,3-dichloro-phenyl LC4 451.23 1.35 3013,4,5-trifluoro-phenyl LC4 437.28 1.36 3023-chloro-5-trifluoromethyl-phenyl LC4 485.3 1.40 3033-trifluoromethyl-phenyl LC6 451.31 4.89 3042-fluoro-3-trifluoromethyl-phenyl LC4 469.26 1.34

EXAMPLE 305cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The compound was prepared in analogy to example 92 usingcis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochlorideinstead of 1-amino-cycloheptanecarboxylic acid methyl esterhydrochloride.

LC/MS (Method LC4): Rt=1.17 min; m/z=466.23 [MH⁺]

In analogy to example 92, the example compounds of the formulae I-11,I-12 and I-13 listed in table 11, in which R¹¹¹, R¹¹² and R¹¹³ have themeanings given in table 11, were prepared.

TABLE 11 Example compounds of the formulae I-11, I-12 and I-13 Reten-tion Exam- For- LC/MS m/z time ple mula R¹¹¹/R¹¹²/R¹¹³ Method [MH⁺][min] 306 I-11 3-trifluoromethoxy-phenyl LC4 467.28 1.39 307 I-123-trifluoromethoxy-phenyl LC4 453.25 1.36 308 I-133-trifluoromethoxy-phenyl LC4 453.25 1.35 309 I-11 2,3-dichloro-phenylLC4 451.21 1.37 310 I-12 2,3-dichloro-phenyl LC4 437.19 1.34 311 I-132,3-dichloro-phenyl LC4 437.17 1.34 312 I-11 3,4,5-trifluoro-phenyl LC4437.25 1.37 313 I-12 3,4,5-trifluoro-phenyl LC4 423.21 1.34 314 I-133,4,5-trifluoro-phenyl LC4 423.22 1.33 315 I-133-chloro-5-trifluoromethyl- LC4 471.22 1.39 phenyl 316 I-113-trifluoromethyl-phenyl LC4 451.27 1.38 317 I-123-trifluoromethyl-phenyl LC4 437.24 1.35 318 I-133-trifluoromethyl-phenyl LC4 437.24 1.34 319 I-123-chloro-4-methoxy-phenyl LC4 433.21 1.32 320 I-133-chloro-4-methoxy-phenyl LC4 433.21 1.31

In analogy to example 92, the compounds of the formulae I-11, I-12 andI-13 listed in table 12, in which R¹¹¹, R¹¹² and R¹¹³ have the meaningsgiven in table 12, can be prepared.

TABLE 12 Compounds of the formulae I-11, I-12 and I-13 Reten- tion Exam-For- LC/MS m/z time ple mula R¹¹¹/R¹¹²/R¹¹³ Method [MH⁺] [min] 321 I-113-chloro-5-trifluoromethyl- phenyl 322 I-12 3-chloro-5-trifluoromethyl-phenyl 323 I-11 2-fluoro-3-trifluoromethyl- phenyl 324 I-122-fluoro-3-trifluoromethyl- phenyl 325 I-13 2-fluoro-3-trifluoromethyl-phenyl 326 I-11 3-chloro-4-methoxy-phenyl LC4 447.17 1.34

In analogy to example 92, the example compounds of the formulae I-14,I-15, I-16 and I-17 listed in table 13, in which R¹¹⁴, R¹¹⁵, R¹¹⁶ andR¹¹⁷ have the meanings given in table 13, were prepared.

TABLE 13 Example compounds of the formulae I-14, I-15, I-16 and I-17Reten- tion Exam- For- LC/MS m/z time ple mula R¹¹⁴/R¹¹⁵/R¹¹⁶/R¹¹⁷Method [MH⁺] [min] 327 I-14 3-trifluoromethoxy-phenyl LC4 466.25 1.40328 I-15 3-trifluoromethoxy-phenyl LC4 466.25 1.39 329 I-163-trifluoromethoxy-phenyl LC4 452.17 1.37 330 I-173-trifluoromethoxy-pheny LC4 452.22 1.36 331 I-143-trifluoromethyl-phenyl LC4 450.2 1.38 332 I-153-trifluoromethyl-phenyl LC4 450.2 1.38 333 I-163-trifluoromethyl-phenyl LC4 436.2 1.35 334 I-173-trifluoromethyl-phenyl LC4 436.17 1.35

In analogy to example 92, the compounds of the formulae I-14, I-15, I-16and I-17 listed in table 14, in which R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ have themeanings given in table 14, can be prepared.

TABLE 14 Compounds of the formulae I-14, I-15, I-16 and I-17 ExampleExample Example Example (formula) (formula) (formula) (formula)R¹¹⁴/R¹¹⁵/R¹¹⁶/R¹¹⁷ 335 (I-14) 336 (I-15) 337 (I-16) 338 (I-17)2,3-dichloro-phenyl 339 (I-14) 340 (I-15) 341 (I-16) 342 (I-17)3,4,5-trifluoro-phenyl 343 (I-14) 344 (I-15) 345 (I-16) 346 (I-17)3-chloro-5-trifluoro- methyl-phenyl 347 (I-14) 348 (I-15) 349 (I-16) 350(I-17) 2-fluoro-3-trifluoro- methyl-phenyl 351 (I-14) 352 (I-15) 353(I-16) 354 (I-17) 3-chloro-4-methoxy- phenyl Reten- tion Exam- For-LC/MS m/z time ple mula R¹¹⁴/R¹¹⁵/R¹¹⁶/R¹¹⁷ Method [MH⁺] [min] 351 I-143-chloro-4-methoxy- LC4 446.21 1.35 phenyl 352 I-15 3-chloro-4-methoxy-LC4 446.21 1.34 phenyl

EXAMPLE 355trans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid

Step 1: trans-1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl esterHydrochloride

4-Ethyl-cyclohexanone was reacted in a Strecker aminonitrile synthesisin analogy to the procedure described in I. L. Munday, J. Chem. Soc.(1961), 4372-4379 to yieldtrans-1-amino-4-ethyl-cyclohexanecarbonitrile. This intermediate (10 g,65.8 mmol) was stirred in 150 ml of 8 N hydrochloric acid under refluxfor 72 h. The volatiles were evaporated, the residue was twiceevaporated with water, resuspended in water and adjusted to pH=6 withsodium hydroxide. After cooling in an ice bath, the precipitate wasfiltered off, washed with water and acetone and dried in vacuo. Theobtained amino acid was suspended in methanol, cooled to −30° C. andthionyl chloride (3 equivalents) was added. The mixture was warmed toroom temperature and stirred overnight. The volatiles were evaporated toyield the title compound.

Step 2:trans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-phenylethanol in the etherification step and using the compound ofstep 1 as amino acid methyl ester hydrochloride intermediate.

LC/MS (Method LC4): Rt=1.33 min; m/z=427.29 [MH⁺]

EXAMPLE 356cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 79 using2-(3-chlorophenyl)ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.29 min; m/z=447.28 [MH⁺]

EXAMPLE 357cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-(3-chlorophenyl)ethanol in the etherification step andcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride (synthesized from 4-ethylcyclohexanone via theBucherer-Bergs hydantoin route in analogy to the procedure described inJ. W. Tsang et al., J. Med. Chem. 27 (1984), 1663-1668) instead of1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.38 min; m/z=461.25 [MH⁺]

EXAMPLE 358cis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-phenylethanol in the etherification step andcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.34 min; m/z=427.3 [MH⁺]

EXAMPLE 359cis-1-{[5-(3,4-Difluoro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 92 using3,4-difluoro-phenylboronic acid in the Suzuki coupling step andcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.36 min; m/z=419.26 [MH⁺]

EXAMPLE 360cis-1-{[5-(3,5-Difluoro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 92 using3,5-difluoro-phenylboronic acid in the Suzuki coupling step andcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.36 min; m/z=419.21 [MH⁺]

EXAMPLE 361(1R,2R)-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylicacid

Step 1: (1R,2R)-1-Amino-2-ethyl-cyclopropanecarboxylic acid ethyl ester

(1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acidethyl ester (400 mg, 1.57 mmol) was dissolved in methanol (5 ml) andadded to a suspension of azodicarboxylic acid dipotassium salt (1.46 g,7.5 mmol; cf. D. J. Pasto et al., Organic Reactions 40 (1991), 91-155)in methanol (10 ml). Acetic acid (1.12 g, 18.8 mmol) was added in thecourse of 10 min and the mixture was stirred for 1 h at roomtemperature. Azodicarboxylic acid dipotassium salt (1.46 g) and aceticacid (1.12 g) were added once again and the mixture stirred for 1 h.LC/MS analysis then indicated complete conversion. The volatiles wereevaporated, the residue was partitioned between EA and a saturatedsodium hydrogencarbonate solution, and the combined organic extractswere dried over sodium chloride, decanted over a small plug of silicagel and evaporated to dryness. The obtained intermediate was dissolvedin a mixture of DCM (5 ml) and TFA (1 ml) and stirred for 1 h at roomtemperature. The volatiles were evaporated, and the residue waspartitioned between diethyl ether and saturated sodium hydrogencarbonatesolution. The combined organic extracts were dried over sodium chloride,decanted and evaporated to dryness to yield the title compound.

Step 2:(1R,2R)-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-(3-chlorophenyl)ethanol in the etherification step and using thecompound of step 1 instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride.

LC/MS (Method LC4): Rt=1.27 min; m/z=419.14 [MH⁺]

EXAMPLE 362trans-4-Ethyl-1-{[5-fluoro-6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

Step 1: 4-(2-Acetoxy-ethoxy)-3-bromo-5-fluoro-benzoic acid methyl ester

3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (500 mg, 2.01 mmol;T. Kline et al., J. Med. Chem. 45 (2002), 3112-3129), potassiumcarbonate (971 mg, 7.03 mmol) and 2-bromoethyl acetate (503 mg, 3.01mmol) were reacted in DMF (5 ml) at room temperature for 72 h. Then themixture was partitioned between EA and 2 N hydrochloric acid, and thecombined organic extracts were dried over sodium chloride, decanted andevaporated to dryness. The raw material was purified by silica gelchromatography (EA/HEP gradient 0:1 to 4:6) to yield the title compound.

¹H-NMR: δ=7.97 (d, 1H); 7.81 (dd, 1H); 4.45-4.40 (m, 2H); 4.33-4.29 (m,2H); 3.85 (s, 3H); 2.01 (s, 3H)

Step 2:trans-4-Ethyl-1-{[5-fluoro-6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronicacid in analogy to step 3 of example 92, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yield5-fluoro-6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylicacid. This intermediate was coupled to the compound of step 1 of example355 in analogy to step 1 of example 3, and the obtained esterintermediate hydrolyzed in analogy to step 4 of example 1 to yield thetitle compound.

LC/MS (Method LC4): Rt=1.32 min; m/z=498.23 [MH⁺]

In analogy to example 3, the example compounds of the formula I-1 listedin table 15 were prepared.

TABLE 15 Example compounds of the formula I-1 Reten- tion Exam- LC/MStime ple R¹⁰¹ Method m/z [min] 363 2-(3-trifluoromethylphenyl)- LC8480.20 2.54 ethyl [MH⁺] 364 2-(2-chlorophenyl)-ethyl LC8 446.18 2.50[MH⁺] 365 2-(3-fluorophenyl)-ethyl LC6 428.08 2.57 [M − H⁺]

By coupling 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid to therespective amino acid methyl ester via the carboxylic acid chlorideroute as described in step 3 of example 1 or the TOTU coupling route asdescribed in step 1 of example 3, the example compounds of the formulaI-2 listed in table 16 were prepared. The amino acid methyl esters orthe amino acids were commercially available or were prepared from therespective ketone in analogy to example 25. In the formulae of thegroups R¹⁰² in table 2 the line crossed with the symbol

represents the free bond via which the group R¹⁰² is bonded to thenitrogen atom of the amide group depicted in formula I-2. I.e., in theformula of the complete molecule the terminal endpoint of the linecrossed with the said symbol ends on the nitrogen atom of the amidegroup.

TABLE 16 Example compounds of the formula I-2 Example

Starting material LC/MS Method m/z [MH⁺] Retention time [min] 366

(a) LC10 468.37 4.10 367

(a) LC6 426.36 4.78 368

(b) LC4 370.15 1.18 (a) The amino acid ester was prepared from therespective ketone. (b) The amino acid ester or amino acid wascommercially available.

In analogy to example 43, by employing the respective ketone instead of4-methyl-cyclohexanone in the initial Strecker aminonitrile step, theexample compounds of the formula I-3 listed in table 17 were prepared.In the formulae of the groups R¹⁰³ in table 17 the line crossed with thesymbol

represents the free bond via which the group R¹⁰³ is bonded to thenitrogen atom of the amide group depicted in formula I-3. I.e., in theformula of the complete molecule the terminal endpoint of the linecrossed with the said symbol ends on the nitrogen atom of the amidegroup.

TABLE 17 Example compounds of the formula I-3 Ex- ample

LC/MS Method m/z [MH⁺] Retention time [min] 369

LC1 480.22 1.81 370

LC10 454.35 3.97 371

LC4 468.34 1.35 372

LC4 426.46 1.3 373

LC4 412.28 1.28 374

LC4 442.13 1.15 (a) Other diastereomer than in example 28, example 29,example 366, example 367, example 33, respectively.

In analogy to example 92, the example compounds of the formula I-23listed in table 18, in which R¹²³ has the meaning given in table 18,were prepared. The respectivecis-1-amino-4-trifluoromethylcyclohexanecarboxylic acid methyl esterhydrochloride was prepared as for example 28

TABLE 18 Example compounds of the formulae I-23 Reten- tion Exam- LC/MSm/z time ple R¹²³ Method [MH⁺] [min] 375 3,4,5-trifluorophenyl LC4477.28 1.32 376 3-trifluoromethylphenyl LC4 491.33 1.35 377 2-fluoro-3-LC4 509.34 1.34 trifluoromethylphenyl 378 2,3-dichlorophenyl LC4 491.211.32 379 3-trifluoromethoxyphenyl LC4 507.2 1.32 380 3-chloro-5- LC4525.16 1.36 trifluoromethylphenyl

In analogy to example 362, the example compounds of the formula I-18listed in table 19, in which R¹¹⁸ has the meaning given in table 19,were prepared.

TABLE 19 Example compounds of the formula I-18 Reten- tion Exam- LC/MSm/z time ple R¹¹⁸ Method [MH⁺] [min] 381 3-chloro-4-methoxy- LC4 494.201.30 phenyl 382 3-trifluoromethoxy-phenyl LC4 514.23 1.34 3833-trifluoromethyl-phenyl LC4 498.31 1.20 384 3,4-difluorophenyl LC4466.24 1.17 385 3,5-difluorophenyl LC4 466.23 1.17

EXAMPLE 386trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

Step 1: 4-(2-Acetoxy-ethoxy)-3-bromo-benzoic acid 2-acetoxy-ethyl ester

3-Bromo-4-hydroxy-benzoic acid (3.00 g, 13.8 mmol), caesium carbonate(9.01 g, 27.6 mmol) and 2-bromoethyl acetate (4.62 g, 27.6 mmol) werestirred in DMF for 3 days at room temperature. Volatiles were evaporatedin vacuo, the remainder was partitioned between ethyl acetate and water,the combined organic extracts were dried over sodium chloride andevaporated to dryness. The raw material was titurated in ether, filteredand dried in vacuo to yield the title compound (4.66 g).

LC/MS (Method LC4): Rt=1.25 min; m/z=389.04 [MH⁺]

Step 2:trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronicacid in analogy to step 3 of example 92, the obtained ester intermediatewas hydrolyzed in analogy to step 4 of example 1 to yield6-(2-Hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylic acid. Thisintermediate was coupled totrans-1-amino-4-ethylcyclohexanecarboxylicacid methylester hydrochloridein analogy to step 1 of example 3, and the obtained ester intermediatewas hydrolyzed in analogy to step 4 of example 1 to yield the titlecompound.

LC/MS (Method LC4): Rt=1.30 min; m/z=480.19 [MH⁺]

In analogy to example 386, the example compounds of the formula I-19listed in table 20, in which R¹¹⁹ has the meaning given in table 20,were prepared.

TABLE 20 Example compounds of the formula I-19 Reten- tion Exam- LC/MSm/z time ple R¹¹⁹ Method [MH⁺] [min] 387 3-trifluoromethyl-phenyl LC4480.21 1.31 388 3,4-difluoro-phenyl LC4 448.19 1.28 3893,5-difluoro-phenyl LC6 448.19 4.52 390 3-trifluoromethoxy-phenyl LC6496.16 4.69 391 3-chloro-4-methoxy- LC4 476.22 1.27 phenyl

EXAMPLE 392trans-1-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester (see example 69)was etherified with 2-[3-(2-hydroxy-ethyl)-phenyl]-ethanol in analogy tostep 1 of example 1. Hydrolysis of the ester group in analogy to step 2of example 1, coupling of the obtained carboxylic acid totrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3 and hydrolysis of themethyl ester in analogy to step 4 of example 1 yielded the titlecompound.

LC/MS (Method LC4): Rt=1.25 min; m/z=474.32 [MH⁺]

EXAMPLE 3931-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 392 using1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride insteadof trans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride.

LC/MS (Method LC4): Rt=1.24 min; m/z=474.29 [MH⁺]

EXAMPLE 394trans-4-Ethyl-1-(3-fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 392 usingtrans-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-methyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.29 min; m/z=488.32 [MH⁺]

EXAMPLE 395trans-4-Ethyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 355 using2-m-tolyl-ethanol in the etherification step.

LC/MS (Method LC3): Rt=4.67 min; m/z=441.31 [MH⁺]

EXAMPLE 396cis-4-Ethyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 357 using2-m-tolyl-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.37 min; m/z=441.36 [MH⁺]

EXAMPLE 397trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 355 using2-(3-chlorophenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.36 min; m/z=461.27 [MH⁺]

EXAMPLE 398trans-4-Ethyl-1-({6-methoxy-5-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-pyridine-3-carbonyl}-amino)-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 355 using2-(3-trifluoromethoxyphenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.38 min; m/z=511.29 [MH⁺]

EXAMPLE 399cis-4-Ethyl-1-({6-methoxy-5-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-pyridine-3-carbonyl}-amino)-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 357 using2-(3-trifluoromethoxyphenyl)-ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.39 min; m/z=511.29 [MH⁺]

EXAMPLE 400cis-1-{[6-Methoxy-5-(2-phenyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 79 using2-phenylethanol instead of 2-m-tolylethanol.

LC/MS (Method LC4): Rt=1.25 min; m/z=413.37 [MH⁺]

EXAMPLE 4011-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 77 using2-(3-chlorophenyl)ethanol instead of 2-m-tolylethanol.

LC/MS (Method LC4): Rt=1.31 min; m/z=447.15 [MH⁺]

EXAMPLE 402cis-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 77 usingcis-1-amino-4-trifluoromethylcyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl esterhydrochloride in the amide coupling step.

LC/MS (Method LC4): Rt=1.28 min; m/z=481.36 [MH⁺]

EXAMPLE 403cis-4-Ethyl-1-{4-methoxy-3-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-benzoylamino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 3 using2-(3-trifluoromethoxyphenyl)-ethanol in the etherification step andcis-1-amino-4-ethylcyclohexanecarboxylicacid methylester hydrochloridein the amide coupling step.

LC/MS (Method LC4): Rt=1.39 min; m/z=510.30 [MH⁺]

EXAMPLE 404cis-1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 3 usingcis-1-amino-4-methylcyclohexanecarboxylic acid methyl esterhydrochloride instead of 1-amino-cycloheptanecarboxylic acid methylester hydrochloride in the amide coupling step.

LC/MS (Method LC3): Rt=4.57 min; m/z=464.21 [MH⁺]

EXAMPLE 405cis-1-{3-[2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 404 using2-(2-fluoro-5-trifluoromethoxyphenyl)ethanol instead of2-(5-chloro-2-fluorophenyl)ethanol in the etherification step.

LC/MS (Method LC4): Rt=1.34 min; m/z=514.27 [MH^(+])

EXAMPLE 406cis-1-(4-Methoxy-3-phenethyloxy-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 404 using2-phenylethanol instead of 2-(5-chloro-2-fluorophenyl)ethanol in theetherification step.

LC/MS (Method LC4): Rt=1.30 min; m/z=412.29 [MH⁺]

In analogy to example 92, the example compounds of the formulae I-10,I-11 and I-12 listed in table 21, in which R¹¹⁰, R¹¹¹ and R¹¹² have themeanings given in table 21, were prepared.

TABLE 21 Example compounds of the formulae I-10, I-11 and I-12 Reten-tion Exam- For- LC/MS m/z time ple mula R¹¹⁰/R¹¹¹ Method [MH⁺] [min] 407I-10 4-fluoro-phenyl LC4 401.23 1.34 408 I-114-chloro-3-trifluoromethyl- LC4 485.23 1.41 phenyl 409 I-103-fluoro-phenyl LC4 401.19 1.34 410 I-12 3,5-difluoro-phenyl LC4 405.141.32 411 I-10 3-fluoro-4-methoxy-phenyl LC4 431.20 1.32 412 I-113-fluoro-4-methoxy-phenyl LC4 431.23 1.31

EXAMPLE 4134-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

Step 1: 5-Bromo-6-chloro-nicotinic acid 2-hydroxy-ethyl ester

5-Bromo-6-chloro-nicotinoyl chloride (W. J. Thompson et al., J. Org.Chem. 49 (1984), 5237-5243, raw material; 7.00 g, apx 50% purity) wasdiluted with dichloromethane (50 ml), ethylenglycol (17 g) was addedslowly and the mixture was stirred at room temperature over night. Themixture was partitioned between ether and water and the aqueous phasewas extracted three times with ether. Each ether extract was washed withnew water. The combined organic layers were dried over sodium chlorideand evaporated to dryness in vacuo to yield the title compound (6.0 g)as raw material.

Step 2: 6-(2-Acetoxy-ethoxy)-5-bromo-nicotinic acid 2-acetoxy-ethylester

Sodium hydride (1.29 g, 60% purity in mineral oil) was dissolved inethylene glycol (25 ml) and the raw material of step 1 was added. Thismixture was stirred at 60° C. for 1 h. Volatiles were evaporated at 95°C., 1 mbar. The remainder was suspended in pyridine (25 ml), aceticanhydride (25 g) was added slowly during 30 minutes with stirring andstirring continued for 1 h. The mixture was partitioned between ethylacetate and water, the organic phase was washed with 2N HCl andsaturated sodium bicarbonate solution, dried over sodium chloride andevaporated to dryness in vacuo.

The remainder was titurated in diethyl ether, cooled in an ice bath andfiltered to yield 2.5 g of the title compound.

¹H-NMR: δ=8.70 (d, 1H); 8.40 (d, 1H); 4.65-4.62 (m, 2H); 4.47-4.45 (m,2H); 4.40-4.37 (m, 2H); 4.36-4.32 (m, 2H); 2.02 (s, 3H); 2.01 (s, 3H)

Step 3:4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The compound of step 2 was coupled to 3-trifluorophenylbenzene boronicacid in analogy to step 3 of example 92, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yield6-(2-Hydroxy-ethoxy)-5-(3-trifluoro methyl-phenyl)-nicotinic acid. Thisintermediate was coupled to cis-1-amino-4-ethyl-cyclohexanecarboxylicacid methyl ester hydrochloride in analogy to step 1 of example 3, andthe obtained ester intermediate was hydrolyzed in analogy to step 4 ofexample 1 to yield the title compound.

LC/MS (Method LC4): Rt=1.30 min; m/z=481.16 [MH⁺]

¹H-NMR: δ=12.2 (s, 1H); 8.64 (d, 1H); 8.24-8.18 (m, 2H); 8.06 (s, 1H);8.01 (d, 1H); 7.78-7.70 (m, 2H); 4.78 (t, 1H); 4.44 (t, 2H); 3.71 (dt,2H); 2.33-2.27 (m, 2H); 1.72-1.52 (m, 4H); 1.30-1.15 (m, 5H); 0.85 (t,3H)

In analogy to example 413, the example compounds of the formula I-20listed in table 22, in which R¹²⁰ has the meaning given in table 22,were prepared.

TABLE 22 Example compounds of the formula I-20 Reten- tion Exam- LC/MSm/z time ple R¹²⁰ Method [MH⁺] [min] 414 3,4-difluoro-phenyl LC4 449.201.27 415 3,5-difluoro-phenyl LC4 449.21 1.27 4163-trifluoromethoxy-phenyl LC4 497.25 1.32 417 3-chloro-4-methoxy- LC4477.24 1.27 phenyl

In analogy to example 119, the compounds of examples 418 and 419 weresynthesized using the respective amino acid methyl ester hydrochloridein the amide coupling step.

EXAMPLE 418trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.0 (s, 1H); 8.0& (s, 1H); 7.48-7.44 (m, 2H); 7.42-7.38 (m,1H); 7.37-7.25 (m, 3H); 7.03 (d, 1H); 4.82 (t, 1H); 4.22 (t, 2H); 4.02(t, 2H); 3.78-3.70 (m, 2H); 3.06 (t, 2H); 2.31-2.22 (m, 2H); 1.68-1.52(m, 4H); 1.32-1.12 (m, 5H); 0.85 (t, 3H)

EXAMPLE 419cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethyl-cyclohexanecarboxylicacid

¹H-NMR: δ=12.1 (s, 1H); 7.97 (s, 1H); 7.49-7.43 (m, 2H); 7.41-7.38 (m,1H); 7.37-7.26 (m, 3H); 7.03 (d, 1H); 4.82 (t, 1H); 4.23 (t, 2H); 4.02(t, 2H); 3.78-3.70 (m, 2H); 3.08 (t, 2H); 2.34-2.24 (m, 2H); 1.68-1.50(m, 4H); 1.27-1.11 (m, 5H); 0.83 (t, 3H)

In analogy to example 119, the compounds of examples 420, 421 and 422were synthesized using 2-phenylethanol in the etherification step andthe respective amino acid methyl ester hydrochloride in the amidecoupling step.

EXAMPLE 420trans-1-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

LC/MS (Method LC4): Rt=1.22 min; m/z=442.30 [MH⁺]

EXAMPLE 421cis-1-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

LC/MS (Method LC4): Rt=1.21 min; m/z=442.29 [MH⁺]

EXAMPLE 4221-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]cycloheptanecarboxylicacid

LC/MS (Method LC4): Rt=1.20 min; m/z=442.27 [MH⁺]

EXAMPLE 423cis-4-Ethyl-1-[(5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 90 usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-methyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.13 min; m/z=471.32 [MH⁺]

EXAMPLE 424trans-4-Ethyl-1-[(5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 90 usingtrans-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-methyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.12 min; m/z=471.33 [MH⁺]

EXAMPLE 425cis-4-Ethyl-1-[(3′-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

Step 1: 3′-Fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acid methyl ester

3-Bromo-4-methoxybenzoic acid methyl ester (500 mg, 2.04 mmol),3-fluoro-4-methoxyphenylboronic acid (381 mg, 2.24 mmol),Tetrakis(triphenylphosphine)-palladium(0) (117 mmol, 0.10 mmol), andsodium bicarbonate (514 mg, 6.12 mmol) were partitioned between toluene(5 ml) and water (5 ml) and stirred in reflux for 36 hours. The mixturewas partitioned between ethyl acetate and water, the combined organicextracts were dried over sodium sulfate and evaporated to dryness. Theraw material was purified by silica gel chromatography with aheptane/ethyl acetate gradient. to yield the title compound (500 mg).

¹H-NMR: δ=7.95 (dd, 1H); 7.82 (d, 1H), 7.38 (dd, 1H); 7.30-7.19 (m, 3H);3.88 (s, 3H); 3.87 (s, 3H), 3.83 (s, 3H).

Step 2:cis-4-Ethyl-1-[(3′-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

Hydrolysis of the ester group in analogy to step 2 of example 1,coupling of the obtained carboxylic acid tocis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3 and hydrolysis of themethyl ester in analogy to step 4 of example 1 yielded the titlecompound.

¹H-NMR: δ=12.1 (br s, 1H); 8.06 (s, 1H); 7.84 (dd, 1H); 7.80 (d, 1H);7.40 (dd, 1H); 7.32 (dd, 1H); 7.23 (dd, 1H), 7.18 (d, 1H); 3.88 (s, 3H);3.83 (s, 3H); 2.85-2.77 (m, 2H); 1.70-1.50 (m, 4H); 1.25-1.10 (m, 5H);0.85 (t, 3H).

EXAMPLE 426cis-4-Ethyl-1-{[6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

Step 1: 6-Methoxy-5-(3-trifluoromethyl-phenyl)-nicotinic acid methylester

5-Bromo-6-methoxy-nicotinic acid methyl ester (1.03 g, 4.18 mmol),3-trifluoromethylbenzeneboronic acid (0.795 g, 4.19 mmol),tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) and sodiumbicarbonate (1.05 g, 12.5 mmol) were partitioned between toluene (10 ml)and water (10 ml) under argon and stirred in reflux for 1 h. Thematerial was partitioned between ethyl acetate and water, the combinedorganic extracts were dried over sodium chloride, filtered over a smallplug of silica and evaporated to dryness. The solid material was tituredwith methanol, filtered and dried in vacuo to yield the title compound(1.4 g) sufficiently pure for further synthesis.

¹H-NMR: δ=8.80 (d, 1H); 8.20 (d, 1H); 7.93 (s, 1H); 7.90 (d, 1H); 7.78(d, 1H); 7.71 (t, 1H); 3.97 (s, 3H); 3.88 (s, 3H).

Step 2: 6-Methoxy-5-(3-trifluoromethyl-phenyl)-nicotinic acidFFC.GFN2.004.4

The compound of step 1 was hydrolysed in analogy to step 2 of example 1to yield the title compound.

¹H-NMR: δ=13.2 (br s, 1H); 8.78 (d, 1H); 8.19 (d, 1H); 7.93 (s, 1H);7.90 (d, 1H); 7.78 (d, 1H); 7.70 (t, 1H); 3.97 (s, 3H).

Step 3:cis-4-Ethyl-1-{[6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid methyl ester as mixture withcis-4-ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid methyl ester

The compound of step 3 (1.09 g, 3.67 mmol) was dissolved in thionylchloride (5 ml) and stirred for 30 minutes at 60° C. Volatiles wereevaporated, the remainder was dissolved in dichloromethane and added toa stirred mixture of cis-1-amino-4-ethylcyclohexanecarboxylic acidmethyl ester hydrochloride (0.813 g, 3.67 mmol) and sodium bicarbonate(1.5 g, 18.3 mmol) in ethyl acetate (25 ml)/water (25 ml). Stirringcontinued over night, phases were separated, the aqueous phase wasextracted twice with ethyl acetate, the combined organic extracts weredried over sodium chloride, decanted and evaporated to dryness in vacuoto yield the title compounds as mixture.

Step 4:cis-4-Ethyl-1-{[6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The compound of step 3 (1.71 g, 3.6 mmol)) was dissolved in dioxane (14ml). 1 M aqueous lithium hydroxide (7 ml) was added, the mixture wasstirred at 60° C. for 1 h, cooled, and partitioned between 2 Nhydrochloric acid and EA. The aqueous phase was extracted with EA, thecombined organic phases were dried over sodium chloride, filtered andevaporated to dryness. The residue was stirred in ethyl acetate (5 ml)and filtered, again to yield the title compound (0.28 g)

¹H-NMR: δ=12.7 (br s, 1H); 8.16 (s, 1H); 8.14-8.05 (m, 2H); 8.01 (d,1H); 7.80-7.55 (m, 3H); 2.4-2.25 (m, 2H); 1.65-1.45 (m, 4H); 1.23-1.00(m, 5H); 0.82 (t, 3H).

EXAMPLE 427(1R,2R)-2-Ethyl-1-[(6-methoxy-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclopropanecarboxylicacid

3-bromo-4-methoxybenzoic acid methyl ester was coupled to3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92,and the obtained ester intermediate was hydrolyzed in analogy to step 4of example 1 to yield 6-methoxy-3′-trifluoromethyl-biphenyl-3-carboxylicacid. This intermediate was coupled to the compound of step 1 of example361 in analogy to step 1 of example 3, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yieldthe title compound.

LC/MS (Method LC4): Rt=1.30 min; m/z=408.14 [MH⁺]

EXAMPLE 428cis-4-Ethyl-1-[(6-formyl-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

Step 1: 6-Methyl-3′-trifluoromethyl-biphenyl-3-carboxylic acid methylester

3-trifluoromethylphenylboronic acid (278 mg, 1.46 mmol),tris(dibenzylideneacetone)-dipalladium(0) (61 mg, 0.066 mmol), potassiumfluoride (255 mg, 4.38 mmol) and tri-tert-butylphosphoniumtetrafluoroborate (46 mg, 0.159 mmol) in a flask were thoroughly flushedwith argon. 3-bromo-4-methylbenzoic acid methyl ester (304 mg, 1.32mmol) was added as solution in dioxane (5 ml). the mixture was stirredat 70° C. for 3 h, filtered over silica and evaporated to dryness. Theraw material was purified by silica gel chromatography with ahetane/ethyl acetate gradient to yield the title compound (323 mg).

¹H-NMR: δ=7.91 (d, 1H); 7.82-7.77 (m, 2H); 7.75-7.70 (m, 3H); 7.51 (d,1H); 3.85 (s, 3H); 2.30 (s, 3H)

Step 2: 6-Dibromomethyl-3′-trifluoromethyl-biphenyl-3-carboxylic acidmethyl ester

The compound of step 1 (1.48 g, 5.03 mmol), N-bromosuccinimide (2.27 g,12.8 mmol) and dibenzoylperoxide (60 mg, 0.25 mmol) were suspended intetrachloromethane and stirred for 3 h in reflux. The material wasfiltered over silica, eluted with diethyl ether and evaporated todryness to yield the title compound as raw material.

Step 3: 6-Formyl-3′-trifluoromethyl-biphenyl-3-carboxylic acid methylester

The compound of step 2 (2.1 g, 4.65 mmol) was dissolved in acetonitrile(25 ml). Silver nitrate (1.97 g, 11.6 mmol) was dissolved in water (3ml) and this solution was added to the acetonitrile solution. Thismixture was stirred for 1 h in reflux. Acetonitrile was evaporated invacuo, the remainder was partitioned between ethyl acetate and water,the combined organic extracts were dried over sodium chloride, filteredover a small plug of silica and evaporated to dryness. A crystallinecrop was yielded on addition of methanol and filtration. The motherliquor was evaporated to dryness and purified by silica gelchromatography with a heptane/ethyl acetate gradient to yield a secondcrop. Both were combined to yield the title compound (1.0 g).

¹H-NMR: δ=9.9 (s, 1H); 8.18 (d, 1H); 8.10 (d, 1H); 8.02 (s, 1H); 7.90(s, 1H); 7.88 (d, 1H); 7.83 (d, 1H); 7.76 (t, 1H); 3.91 (s, 3H)

Step 4:cis-4-Ethyl-1-[(6-formyl-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound of step 3 was hydrolysed in analogy to step 4 ofexample 1. This intermediate was coupled tocis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloridein analogy to step 1 of example 3, and the obtained ester intermediatewas hydrolyzed in analogy to step 4 of example 1 to yield the titlecompound.

LC/MS (Method LC4): Rt=1.36 min; m/z=448.18 [MH⁺]

EXAMPLE 429trans-4-Ethyl-1-[(6-formyl-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

This compound was synthesized in analogy to example 428 usingtrans-1-amino-4-ethylcyclohexanecarboxylic acid methyl esterhydrochloride in the amide coupling step.

LC/MS (Method LC4): Rt=1.35 min; m/z=448.15 [MH⁺]

EXAMPLE 430cis-4-Ethyl-1-[(6-hydroxymethyl-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The compound of example 429 (21 mg, 0.047 mmol) was dissolved intetrahydrofurane (1 ml), cooled in an ice bath, sodium borohydride (2mg, 0.047 mmol) was added and thereafter methanol (0.2 ml) was addedslowly with stirring. After 45 minutes, the mixture was partitionedbetween ethyl acetate and 2N hydrochloric acid, the combined organiclayers were dried over sodium chloride and evaporated to dryness. Theremainder was titured with heptane/diethylether and filtered to yieldthe title compound as white solid.

LC/MS (Method LC4): Rt=1.30 min; m/z=450.22 [MH⁺]

EXAMPLE 431trans-4-Ethyl-1-[(6-hydroxymethyl-3′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

This compound was synthesized in analogy to example 430 using the titlecompound of example 429 instead of example 428.

LC/MS (Method LC4): Rt=1.30 min; m/z=450.20 [MH⁺]

EXAMPLE 432trans-4-Ethyl-1-{[6-(3-hydroxy-propyl)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

Step 1 6-(2-Carboxy-vinyl)-3′-trifluoromethyl-biphenyl-3-carboxylic acidmethyl ester

The compound of step 3 of example 428 (400 mg, 1.30 mmol), malonic acid(262 mg, 2.52 mmol) and piperidine (16 mg, 0.19 mmol) were dissolved inpyridine (0.7 ml) and stirred in reflux for 1 h. The material waspartitioned between 2N hydrochloric acid and ethyl acetate (product isonly sparingly soluble). The combined organic extracts were dried oversodium chloride and evaporated to dryness to yield the title compound.

¹H-NMR: δ=12.55 (s, 1H); 8.09 (d, 1H); 8.03 (d, 1H); 7.92 (s, 1H); 7.87(d, 1H); 7.76 (t, 1H); 7.74-7.68 (m, 2H); 7.40 (d, 1H); 7.61 (d, 1H);3.88 (s, 3H)

LC/MS (Method LC4): Rt=1.30 min; m/z=349.16 [M−H⁺]

Step 2: 6-(2-Carboxy-ethyl)-3′-trifluoromethyl-biphenyl-3-carboxylicacid methyl ester

The compound of step 1 (400 mg, 1.14 mmol) and Palladium (10%) oncharcoal (23 mg) were suspended in methanol (30 ml). The mixture washydrogenated for 3 h at 4 bar hydrogen pressure, subsequently filteredover Celite and evaporated to dryness to yield the title compound (372mg).

¹H-NMR: δ=12.2 (br s, 1H); 7.95 (d, 1H); 7.81 (d, 1H); 7.78-7.63 (m,4H); 7.57 (d, 1H); 3.84 (s, 1H); 2.80 (t, 2H); 2.45 (t, 2H)

LC/MS (Method LC4): Rt=1.29 min; m/z=351.18 [M−H⁺]

Step 3: 6-(3-Hydroxy-propyl)-3′-trifluoromethyl-biphenyl-3-carboxylicacid methyl ester

The compound of step 2 (150 mg, 0.428 mmol) was dissolved in THF.N-methylmorpholine (56 mg, 0.556 mmol) and isobutylchloroformate (70 mg,0.514 mmol) were added at room temperature. After stirring for 2minutes, the mixture was filtered and rinsed with THF. Sodiumborohydride (65 mg, 1.71 mmol) was added to the filtrate and thereafterslowly methanol until intensive foaming indicated the start of thereaction. After 5 minutes the reaction was complete as indicated byLC-MS analytics. Volatiles were evaporated in vacuo, the remainder waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution, the combined organic extracts were dried oversodium chloride and evaporated to dryness. This raw material waspurified by silica gel chromatography with a hetpane/ethyl acetategradient to yield the title compound (106 mg)

¹H-NMR: δ=7.95 (dd, 1H); 7.80 (d, 1H); 7.75-7.66 (m, 4H); 7.52 (d, 1H);4.40 (t, 1H); 3.85 (s, 3H); 3.30-3.25 (m, 2H); 2.64-2.58 (m, 2H);1.62-1.55 (m, 2H);

Step 4:4-Ethyl-1-{[6-(3-hydroxy-propyl)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound of step 3 was hydrolysed in analogy to step 4 ofexample 1. This intermediate was coupled totrans-1-amino-4-ethylcyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yieldthe title compound.

LC/MS (Method LC4): Rt=1.32 min; m/z=478.22 [MH⁺]

EXAMPLE 433cis-4-Ethyl-1-{[6-(3-hydroxy-propyl)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 432 usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-ethyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.32 min; m/z=478.20 [MH⁺]

EXAMPLE 434cis-1-{[6-(3-Hydroxy-propyl)-3′-trifluoromethyl-biphenyl-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 432 usingcis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-ethyl-cyclohexanecarboxylicacid methyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.29 min; m/z=464.24 [MH⁺]

EXAMPLE 435cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

Step 1: 5-[2-(3-Chloro-phenyl)-ethoxy]-nicotinic acid ethyl ester

5-Hydroxy-nicotinic acid ethyl ester and 2-(3-chlorophenyl)ethanol wereetherified in a Mitsunobu reaction in analogy to step 3 of example 3 toyield the title compound.

LC/MS (Method LC4): Rt=1.36 min; m/z=306.12 [MH⁺]

Step 2:5-[2-(3-Chloro-phenyl)-ethoxy]-4-ethyl-4H-pyridine-1,3-dicarboxylic acid3-ethyl ester 1-phenyl ester

The compound of step 1 (100 mg, 0.327 mmol) was dissolved in THF (1.5ml) and the mixture was cooled to −30° C. Phenyl chloroformate (77.6 mg,0.49 mmol) was added and the mixture was stirred for 10 minutes. Ethylmagnesiumbromide (0.589 ml, 1M in THF) was added at −30° C. and themixture was stirred for 30 minutes, partitioned between diethylether andaqueous ammonium chloride solution, the combined organic extracts weredried over sodium chloride and evaporated to dryness in vacuo. The rawmaterial was purified by silica gel chromatography with a heptane/ethylacetate gradient to yield the title compound (84 mg).

LC/MS (Method LC4): Rt=1.51 min; m/z=456.19 [MH⁺]

Step 3: 5-[2-(3-Chloro-phenyl)-ethoxy]-4-ethyl-nicotinic acid ethylester

The title compound of step 2 (80 mg, 0.175 mmol)) was dissolved indichloromethane. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35mmol) was added and the mixture was stirred over night at roomtemperature. The mixture was partitioned between ethyl acetate andsaturated sodium hydrogencarbonate solution with addition of some sodiumsulfit. The combined organic extracts were dried over sodium chlorideund avaporated to dryness in vacuo. The material was titured withdiethyl ether, the solid material was separated by suction filtration,the filtrate was evaporated to dryness, again, to yield the titlecompound.

LC/MS (Method LC6): Rt=5.01 min; m/z=334.11 [MH⁺]

Step 4:cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound of step 3 was hydrolysed in analogy to step 2 ofexample 1, for extraction purpose, the aqueous phase was neutralised butnot acidified. The crude acid was titured with ether and filtered butwas reacted further as raw material withcis-1-amino-4-methylcyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yieldthe title compound.

LC/MS (Method LC4): Rt=1.34 min; m/z=445.18 [MH⁺]

EXAMPLE 436trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 435 usingtrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of cis-1-amino-4-methyl-cyclohexanecarboxylic acidmethyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.33 min; m/z=445.17 [MH⁺]

EXAMPLE 437cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 435 usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of cis-1-amino-4-methyl-cyclohexanecarboxylic acidmethyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.38 min; m/z=459.20 [MH⁺]

EXAMPLE 438trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 435 usingtrans-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of cis-1-amino-4-methyl-cyclohexanecarboxylic acidmethyl ester hydrochloride.

LC/MS (Method LC4): Rt=1.23 min; m/z=459.26 [MH⁺]

EXAMPLE 439trans-1-({5-Acetyl-4-[2-(3-chloro-phenyl)-ethoxy]-thiophene-2-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

5-Acetyl-4-hydroxythiophene-2-carboxylic acid methyl ester and2-(3-chlorophenyl)ethanol were etherified in a Mitsunobu reaction inanalogy to step 3 of example 3. This intermediate was hydrolysed inanalogy to step 2 of example 1, coupled withtrans-1-amino-4-ethylcyclohexanecarboxylic acid methyl esterhydrochloride in analogy to step 1 of example 3, and the obtained esterintermediate was hydrolyzed in analogy to step 4 of example 1 to yieldthe title compound.

LC/MS (Method LC4): Rt=1.37 min; m/z=478.15 [MH⁺]

EXAMPLE 440trans-1-({4-[2-(3-Chloro-phenyl)-ethoxy]-5-ethyl-thiophene-2-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid

5-Acetyl-4-[2-(3-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acidmethyl ester (78 mg, 0.23 mmol) was dissolved in 0.5 M methanolichydrogen chloride and hydrogenated with 15 mg Palladium 10% on charcoalat room temperature with 3 bar hydrogen pressure for 14 days. Themixture was filtered over Celite, evaporated to dryness in vacuo andpurified by silica gel chromatography with a heptane/ethyl acetategradient. This intermediate was hydrolysed in analogy to step 2 ofexample 1, coupled with trans-1-amino-4-ethylcyclohexanecarboxylic acidmethyl ester hydrochloride in analogy to step 1 of example 3, and theobtained ester intermediate was hydrolyzed in analogy to step 4 ofexample 1 to yield the title compound.

LC/MS (Method LC4): Rt=1.31 min; m/z=464.22 [MH⁺]

EXAMPLE 441trans-4-Ethyl-1-{[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-cyclohexanecarboxylicacid

Trans-4-ethyl-1-methylaminocyclohexanecarboxylic acid methyl esterhydrochloride was synthesized in via a Strecker aminonitrile synthesisusing N-methylamine hydrochloride instead of ammonium chloride,subsequent acidic hydrolysis of the nitrile to the carboxylic acid andacidic esterificationin in methanol. This intermediate was coupled to4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid chloride in analogy to step3 of example 1, and the obtained ester intermediate was hydrolyzed inanalogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt=1.39 min; m/z=454.33 [MH⁺]

EXAMPLE 442(R,S)-trans-4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylicacid

Step 1: 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethyl ester

4.0 g 3-Formyl-4-hydroxybenzoic acid, 9.6 g1-(2-Bromo-ethyl)-3-methyl-benzene, and 13.3 g K₂CO₃ were added to 100ml of anhydrous DMF and stirred at 90° C. for 14 h. Then 300 ml of waterwere added, and extracted three times with 200 ml EA each. The organiclayer was then washed with 200 ml of water, dried using MgSO₄, andevaporated yielding 8.0 g of the title compound that was used withoutfurther purification.

Step 2: 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid

8.0 g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethylester and 1.7 g of LiOH (Monohydrate) were stirred in 30 ml of THF and 2ml of water at room temperature for 16 h. Then, an additional 1 g ofLiOH (monohydrate) was added and the mixture stirred at room temperaturefor 4 h. Then, 100 ml of water were added, the THF evaporated and theaqueous layer was washed twice with diisopropylether, 100 ml each. Theaqueous layer was then acidified to pH=3 using aqueous HCl-solution andthe crude product collected by filtration. Chromatography on silica gelusing a gradient EA/HEP to EA yielded 1.2 g of the title compound thatwas used without further purification.

Step 3: (R,S)4-(2-m-Tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoic acid

0.75 g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid, 8.9 mg of1,3-Bis(1-adamantyl)imidazol-2-ylidene, and 1.9 g of(Trifluormethyl)trimethylsilane were dissolved in 10 ml of anhydrous DMFand stirred at room temperature for 24 h. Then, another 5 mg of1,3-Bis(1-adamantyl)imidazol-2-ylidene and 1.0 g of(Trifluormethyl)trimethylsilane were added and stirring was continued atroom temperature for 24 h. Then, 10 ml of a 2n aqueous solution of HClwere added and the mixture was stirred at room temperature for 4 h.Then, 50 ml of water were added and the mixture extracted tree timesusing 30 ml EA each. The organic layer was dried using MgSO₄ and thesolvent evaporated to yield 0.7 g of the title compound that was usedwithout further purification.

Step 4:4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized form (R,S)4-(2-m-Tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoic acidand trans-1-Amino-4-methyl-cyclohexanecarboxylic acid methyl ester inanalogy to example 126, step 4. R_(f) (EA/HEP 1:2)=0.28

Step 5:4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylicacid

170 mg of4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]-cyclohexanecarboxylicacid methyl ester and 28 mg of lithium hydroxide were stirred in 50 mlof methanol and 1 ml of water for 5 h at 40° C. The reaction mixture wasthen diluted using 10 ml of water, the methanol evaporated and acidifiedto pH=2 using aqueous NaHSO₄-solution. The mixture was then stirred for30 minutes at room temperature, the product isolated by filtration anddried in vacuo to yield 138 mg of the title compound.

LC/MS (Method LC4): Rt=1.32 min. m/z=494.29 [MH⁺]

EXAMPLE 443trans-1-{[3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

Step 1: 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl ester

1.0 g of Methyl 4-fluoro-3-nitrobenzoate, 1.6 g of3,3-Difluoro-cyclobutanol, and 3.3 g of Cs₂CO₃ were stirred in 10 ml ofanhydrous DMF for 7 h at 60° C. The reaction mixture was then pouredinto 100 ml of water and extracted three times using 30 ml of EA each.The organic layer was dried using MgSO₄ and volatiles were evaporated toyield 1.4 g of the title compound that was used without furtherpurification.

Step 2: 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester

1.4 g of 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl esterwere dissolved using 50 ml of EA and 10 ml of acetic acid, 200 mg ofPd/C 10% (50% water) added and hydrogenated under an atmosphere ofhydrogen at normal pressure for 16 h at room temperature. The reactionmixture was filtrated, 100 ml of EA added and washed twice using 30 mlof a saturated aqueous Na₂CO₃-solution. The organic layer was driedusing MgSO₄ and volatiles were evaporated to yield 1.0 g of the titlecompound that was used without further purification.

Step 3: 3-Bromo-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester

1.0 g of 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl esterwas dissolved in 100 ml of half-concentrated aqueous HBr-solution. Then,a solution of 295 mg NaNO₂ in 5 ml of water was added dropwise at 0° C.Stirring was continued at 0° C. for 15 minutes. Then, a solution of 558mg CuBr in 10 ml of half-concentrated aqueous HBr-solution was addeddropwise and the reaction mixture was stirred for 2 h at roomtemperature. Then, the reaction mixture was extracted three times using100 ml of EA each. The organic layer was then washed three times using100 ml of a saturated aqueous NaHCO₃-solution, dried using MgSO₄ andvolatiles were evaporated to yield 150 mg of the title compound that wasused without further purification.

Step 4:3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylicacid methyl ester

150 mg of 3-Bromo-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methylester, 113 mg of 3-chloro-4-methoxyphenylboronic acid, 129 mg K₂CO₃, 10mg of palladium(II)acetate, and 25 mg of triphenylphosphine weredissolved using 10 ml of DMF and 0.5 ml of water. The reaction mixturewas stirred at 120° C. for 2 h, then cooled to room temperature, 50 mlof water added and extracted three times using 30 ml of EA each. Theorganic layer was dried using MgSO₄ and volatiles were evaporated.Chromatography on silica gel using EA/HEP 1:5 yielded 90 mg of the titlecompound, viscous oil.

R_(f) (EA/HEP 1:5)=0.37

Step 5:3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylicacid

85 mg of3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylicacid methyl ester and 14 mg of LiOH (monohydrate) were dissolved using 5ml of methanol and 0.5 ml of water. The mixture was stirred for 15 h atroom temperature. Then, 14 mg of LiOH (monohydrate) were added and thereaction mixture stirred for 24 h at room temperature. Then, 10 ml ofwater were added and the methanol evaporated. The mixture was thenacidified to pH=2 using aqueous NaHSO₄-solution. The mixture was stirredfor 30 minutes at room temperature. The product was then collected byfiltration and dried in vacuo to yield 65 mg of the title compound thatwas used without further purification.

Step 6:1-{[3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized form3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carboxylicacid and trans-1-Amino-4-methyl-cyclohexanecarboxylic acid methyl esterin analogy to example 126, step 4.

R_(f) (EA/HEP 1:1)=0.40

Step 7:Trans-1-{[3′-Chloro-6-(3,3-difluoro-cyclobutoxy)-4′-methoxy-biphenyl-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt=1.35 min. m/z=508.18 [MH⁺]

EXAMPLE 4441-[(2′,6′-Difluoro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

Step 1: 3-Bromo-4-trifluoromethyl-benzoic acid

5.0 g of 3-amino-4-trifluoromethyl-benzoic acid were dissolved using 50ml of acetic acid. Then, 50 g of ice and 50 ml of a saturated aqueousHBr-solution were added and a solution of 2.0 g NaNO₂ in 10 ml of waterwas added dropwise at 0° C. The reaction mixture was then stirred atroom temperature for 10 minutes. Then, the reaction mixture was addeddropwise to a suspension of 7.0 g CuBr and 10.9 g CuBr₂ in 100 ml of ahalf-concentrated aqueous solution of HBr. The resulting mixture wasthen stirred for 2 h at room temperature, then diluted using 21 ofwater, stirred for 1 h and finally the precipitate was isolated byfiltration. The precipitate was dried in vacuo to yield 5.2 g of thetitle compound that was used without further purification.

Step 2:1-(3-Bromo-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized form3-Bromo-4-trifluoromethyl-benzoic acid andtrans-1-Amino-4-methyl-cyclohexanecarboxylic acid methyl ester inanalogy to example 126, step 4.

R_(f) (EA/HEP 1:2)=0.31

Step 3:1-[(2′,6′-Difluoro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid methyl ester

300 mg of1-(3-Bromo-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylicacid methyl ester, 267 mg of 2,6-difluoro-4-methoxyphenylboronic acid,65 mg of tris(dibenzylideneacetone)di-palladium(0), 96 mg ofbis(2-dicyclohexylphosphinophenyl)ether, 453 mg of K₃PO₄, and 1 g ofmolecular sieve 4 Å were added to 10 ml of toluene. The mixture was madeoxygen-free by passing argon through it. Then, the mixture was kept at160° C. under microwave irradiation for 2 h. Then, 267 mg of2,6-difluoro-4-methoxyphenylboronic acid, 65 mg oftris(dibenzylideneacetone)di-palladium(0), 96 mg ofbis(2-dicyclohexylphosphinophenyl)ether were added and the mixture waskept at 160° C. under microwave irradiation for 2 h. The mixture wascooled to room temperature and 100 ml of EA added. The mixture was thenwashed twice using 20 ml of a saturated aqueous Na₂CO₃-solution each.The organic layer was dried using MgSO₄ and the solvent evaporated.Chromatography on silica gel using EA/HEP 1:5 yielded 16 mg of the titlecompound, viscous oil.

Step 4:1-[(2′,6′-Difluoro-4′-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt=1.34 min. m/z=472.14 [MH⁺]

EXAMPLE 4451-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

Step 1: 3-Chloro-2,6-difluoro-4-methoxyphenylboronic acid

5.1 g of 2,2,6,6-tetramethylpiperidine were dissolved using 200 ml ofanhydrous THF. 12.4 ml of a 2.7M solution of n-butyllithium in heptanewere added at −10° C. and the mixture was stirred for 10 minutes at −10°C. The mixture was then cooled to −70° C. and a solution of 5.0 g2-chloro-3,5-difluoroanisole in 40 ml of anhydrous THF added dropwise at−70° C. Stirring was continued for 1 h at −75° C. Then, 7.9 g oftriisopropyl borat were added and the mixture was allowed to warm toroom temperature. Stirring was continued for 1 h at room temperature.Then, the reaction mixture was poured into 200 ml of a saturated aqueousNaHSO₄-solution and extracted twice using 100 ml EA each. The organiclayer was washed using 100 ml of a saturated aqueous NaHSO₄-solution,dried using MgSO₄ and evaporated to yield 5.6 g of the title compoundthat was used without further purification.

Step 2:1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acidmethyl ester

The title compound was synthesized form 3-bromo-4-methoxy-benzoic acidand trans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester inanalogy to example 126, step 4.

R_(f) (EA/HEP 1:2)=0.12

Step 3:1-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid methyl ester

300 mg of1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acidmethyl ester, 36 mg of tris(dibenzylideneacetone)di-palladium(0), 150 mgof KF, 27 mg of tri-tert-butylphosphonium tetrafluoroborate, and 347 mgof 3-Chloro-2,6-difluoro-4-methoxyphenylboronic acid were suspendedusing 5 ml of anhydrous dioxane and oxygen was removed by passing argonthrough. Then, 12 mg of N,N-diisopropylethylamine were added and againargon passed through the suspension. Stirring was continued for 24 h atroom temperature. The reaction mixture was then filtered and evaporated.The residue was purified by preparative RP HPLC (water/ACN gradient) toyield 150 mg of the title compound, viscous oil.

Step 4:1-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

150 mg of1-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid methyl ester and 25 mg NaOH were dissoled using 5 ml of dioxane and0.5 ml of water. The mixture was stirred at 80° C. for 6 h. Then, 15 mlof water were added, the dioxane evaporated and acidified to pH=3 usingaqueous NaHSO₄-solution. The mixture was stirred for 30 minutes at roomtemperature. The product was then isolated by filtration and dried invacuo to yield 110 mg of the title compound.

LC/MS (Method LC4): Rt=1.32 min. m/z=468.16 [MH⁺]

EXAMPLE 446Trans-1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

Step 1: 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester

3.9 g of 3-fluoro-4-hydroxy-benzoic acid methyl ester were dissolvedusing 25 ml of acetic acid and 25 ml of DCM. The mixture was cooled to0° C. and 1.4 ml bromine added slowly (30 minutes) at 0° C. Stirring wascontinued at room temperature for 18 h. Then, 200 ml of EA and asolution of 7.6 g Na₂SO₃ in 50 ml of water were added and the resultingmixture was stirred for 10 minutes at room temperature. The layers wereseparated, and the organic layer was washed using first 50 ml of waterand second 50 ml of a saturated aqueous NaCl-solution. The organic layerwas dried using MgSO₄ and evaporated to yield 5.0 g of the titlecompound that was used without further purification.

Step 2: 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester

5.0 g of 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester weredissolved using 50 ml of acetone. Then, 8.3 g of K₂CO₃ and 2.5 ml ofCH₃I were added and the reaction mixture stirred at room temperature for48 h. The reaction mixture was then filtrated and evaporated.Chromatography on silica gel using EA/HEP 1:2 yielded 2.0 g of the titlecompound, oil.

Step 3: 3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acidmethyl ester

500 mg of 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester, 532 mgof 3-chloro-4-methoxyphenylboronic acid, 110 mg oftetrakis(triphenylphosphine) palladium(0), and 2.5 g Cs₂CO₃ weredissolved using 16.5 ml of DMF and 3.5 ml of water. The reaction mixturewas stirred at 45° C. for 2 h and then poured into 75 ml of water. Thereaction mixture was then extracted three times using 50 ml of EA each.The organic layer was washed twice using 25 ml of a half-saturatedaqueous NaCl-solution, dried using MgSO₄ and evaporated. Chromatographyon silica gel using EA/HEP 1:3 yielded 500 mg of the title compound,viscous oil.

Step 4: 3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acid

500 mg of 3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acidmethyl ester were dissolved using 10 ml of methanol and 1.8 ml of a 1Maqueous NaOH-solution added. The reaction mixture was stirred at 60° C.for 5 h and was then allowed to cool to room temperature. The reactionmixture was then poured into 25 ml of water and acidified to pH=4 usingaqueous NaHSO₄-solution. The mixture was extracted three times using 20ml of EA each. The organic layer was dried using MgSO₄ and evaporated toyield 430 mg of the title compound that was used without furtherpurification.

Step 5:1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized form3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acid andtrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester inanalogy to example 126, step 4.

Step 6:1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized form1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid methyl ester in analogy to example 126, step 5.

LC/MS (Method LC4): Rt=1.34 min. m/z=450.11 [MH⁺]

EXAMPLE 447Cis-1-[(3′-chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylicacid

The title compound synthesized in analogy to example XX+4 usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester instead oftrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester.

LC/MS (Method LC4): Rt=1.38 min. m/z=464.14 [MH⁺]

EXAMPLE 448Cis-1-[(3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound synthesized in analogy to example 446 usingcis-1-Amino-4-trifluoromethyl-cyclohexanecarboxylic acid methyl esterhydrochloride instead of trans-1-amino-4-methyl-cyclohexanecarboxylicacid methyl ester.

LC/MS (Method LC4): Rt=1.34 min. m/z=504.1 [MH⁺]

EXAMPLE 4491-[3-(5-Chloro-6-methoxy-pyridin-3-yl)-5-fluoro-4-methoxy-benzoylamino]-4-methyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 446, but using5-Chloro-6-methoxy-pyridine-3-boronic acid instead of3-chloro-4-methoxyphenylboronic acid in step 3

LC/MS (Method LC4): Rt=1.34 min. m/z=451.12 [MH⁺]

EXAMPLE 4501-[3-(5-Chloro-6-methoxy-pyridin-3-yl)-5-fluoro-4-methoxy-benzoylamino]-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 449, but usingcis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester instead oftrans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester.

LC/MS (Method LC4): Rt=1.38 min. m/z=465.14 [MH⁺]

EXAMPLE 4511-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to examples 446 and 448,but using

5-Bromo-nicotinic acid methyl ester instead of3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester

LC/MS (Method LC4): Rt=1.24 min. m/z=457.11 [MH⁺]

EXAMPLE 4521-(3-Indol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

Step 1: 3-Amino-4-trifluoromethyl-benzoic acid methyl ester

2.5 g of 3-Amino-4-trifluoromethyl-benzoic acid were dissolved using 50ml of diethyl ether and 25 ml of methanol. Then, 6.1 ml of a 2M solutionof trimethylsilyldiazomethane in hexane were added at 10-20° C. Thereaction mixture was stirred at room temperature for 1 h. Then, 6.1 mlof a 2M solution of trimethylsilyldiazomethane in hexane were added at10-20° C. The reaction mixture was stirred at room temperature for 1 h.The reaction mixture was then evaporated. Chromatography on silica gelusing EA/HEP 1:2 yielded 2.3 g of the title compound, viscous oil.

Step 2: 3-Indol-1-yl-4-trifluoromethyl-benzoic acid methyl ester

690 mg of 3-Amino-4-trifluoromethyl-benzoic acid methyl ester, 650 mg ofK₂CO₃, 30 mg of CuI, and 28 mg of N,N′-dimethylethylendiamine weresuspended using 4.1 ml of anhydrous toluene. 410 mg ofo-bromo-(2-bromo)vinylbenzene were added and the reaction mixturestirred at 110° C. for 14 h. The reaction mixture was allowed to cool toroom temperature, 50 ml of EA added, filtrated, and evaporated.Chromatography on silica gel using EA/HEP (gradient) yielded 220 mg ofthe title compound, viscous oil.

Step 3:1-(3-Indol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylicacid methyl ester

The title compound synthesized in analogy to example 126, step 4.

Step 4:1-(3-Indol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylicacid

The title compound synthesized in analogy to example 126, step 5.

LC/MS (Method LC4): Rt=1.23 min. m/z=445.22 [MH⁺]

EXAMPLE 4531-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 451.

LC/MS (Method LC4): Rt=1.17 min. m/z=417.09 [MH⁺]

EXAMPLE 454Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid

Step 1: 2,2-Difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylicacid

200 ml of anhydrous diethyl ether were poured to 1.9 g of Mg turningsand 2.0 g of(6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J.Org. Chem. 2004, 1, 64) added. The mixture was then stirred at 35° C.for 30 minutes. Then, the heating was shut down and 23.4 g of(6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was addeddropwise to the stirred mixture at a rate that ensured gentle boiling.Stirring was continued at 35° C. for 2 h. Then, the mixture was intenslystirred at room temperature under an excess of anhydrous CO₂ for 2 h.The reaction mixture was then poured into 300 ml of a saturated aqueousNH₄Cl-solution, acidified to pH=3 using aqueous HClI-solution and theorganic layer separated. The aqueous layer was then extracted using 200ml of diethyl ether. The combined organic layer was dried using MgSO₄and evaporated to yield 22.0 g of the title compound that was usedwithout further purification.

Step 2: 2,2-Difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylicacid methyl ester

22.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylicacid were dissolved using 200 ml of diethyl ether and 100 ml ofmethanol. Then, 35.0 ml of a 2M solution of trimethylsilyldiazomethanewas added at 10° C.-20° C. Stirring was continued for 1 h at roomtemperature and the mixture then evaporated. Chromatography on silicagel using EA/HEP 1:10 yielded 17.0 g of the title compound, colorlessoil. R_(f) (EA/HEP 1:20)=0.39

Step 3: 2,2-Difluoro-7-iodo-benzo[1,3]dioxole-5-carboxylic acid methylester

17.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylicacid methyl ester were dissolved using 100 ml of CCl₄ and 2.9 ml of ICIadded. The mixture was then stirred for 3 h at 77° C., 1.5 ml of ICIadded and stirred for 2 h at 77° C. The mixture was then allowed to coolto room temperature, 200 ml of CH₂Cl₂ added, and washed three timesusing 300 ml of a saturated aqueous Na₂SO₃-solution each. The organiclayer was then dried using MgSO₄ and evaporated. Chromatography onsilica gel using EA/HEP 1:20 yielded 10.2 g of the title compound,colorless oil. R_(f) (EA/HEP 1:20)=0.30

Step 4:7-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid methyl ester

8.5 g of 2,2-difluoro-7-iodo-benzo[1,3]dioxole-5-carboxylic acid methylester, 11.2 g of bis(neopentyl glycolato)diboron, 9.8 g of K₂CO₃, and1.8 g of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridewere added to 100 ml of anhydrous DMSO and the mixture stirred at 80° C.for 5 h. The mixture was then allowed to cool to room temperature, 500ml of EA added, and washed three times using 300 ml of water each. Theorganic layer was dried using MgSO₄ and evaporated to yield 8.2 g of thetitle compound that was used without further purification.

Step 5: 2,2-Difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acidmethyl ester

6.0 g of7-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid methyl ester were dissolved using 200 ml of methanol and 30 ml of a33% aqueous solution of H₂O₂ added. Stirring was continued for 30minutes at room temperature. The reaction mixture was then concentratedto 20 ml and 100 ml of water and 100 ml of a saturated aqueousNaCl-solution added. The reaction mixture was then extracted three timesusing 100 ml of CH₂Cl₂ each, dried using MgSO₄, and evaporated.Chromatography on silica gel using EA/HEP 1:4 yielded 1.8 g of the titlecompound, colorless oil.

Step 6: 2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylicacid methyl ester

1.8 g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acidmethyl ester, 4.6 g of 1-(bromo-ethyl)-3-methyl-benzene, and 3.2 g ofK₂CO₃ were added to 70 ml of anhydrous DMF and the reaction mixturestirred at 80° C. for 3 h. The reaction mixture was then allowed to coolto room temperature, 300 ml of water added and extracted three timesusing 100 ml of EA each. The organic layer was then dried using MgSO₄and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded2.4 g of the title compound, colorless oil. R_(f) (EA/HEP 1:4)=0.32

Step 7: 2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylicacid

The title compound was synthesized from2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acidmethyl ester in analogy to example 443, step 5.

Step 8:Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized from2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acidand cis-1-amino-4-trifluoromethyl-cyclohexanecarboxylic acid methylester in analogy to example 126, step 4.

R_(f) (EA/HEP 1:2)=0.22

Step 9:Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid

100 mg ofcis-1-{[2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester were dissolved using 10 ml of methanol, 10 ml of THF,and 2 ml of water. 15.4 mg of lithium hydroxide monohydrate were thenadded and the reaction mixture was stirred at room temperature for 14 h.Stirring was continued for 5 h at 40° C. Then, the mixture wasevaporated, 10 ml of water added and acidified to pH=2 using aqueousNaHSO₄— solution. The resulting mixture was then stirred for 1 h at roomtemperature, and extracted three times using 10 ml of CH₂Cl₂. Theorganic layer was then dried using MgSO₄ and evaporated to yield 55 mgof the title compound, amorphous solid.

LC/MS (Method LC4): Rt=1.38 min. m/z=530.33 [MH⁺]

EXAMPLE 4551-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylicacid

The title compound was synthesized in analogy to example 454.

LC/MS (Method LC4): Rt=1.38 min. m/z=476.36 [MH⁺]

EXAMPLE 456Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 454.

LC/MS (Method LC4): Rt=1.42 min. m/z=490.38 [MH⁺]

EXAMPLE 4571-[(6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylicacid

Step 1: 3-(3-Bromo-phenyl)-oxetane

4.7 g of 3-bromophenylboronic acid, 219 mg of NiI₂, 4.3 g of sodiumbis(trimethylsilyl)amide, and 106 mg of trans-2-aminocyclohexanolhydrochloride were added to 14 ml of anhydrous 2-propanol and oxygenremoved by passing argon through the mixture for 10 minutes. Then, asolution of 2.2 g of 3-iodo-oxetane in 1 ml of anhydrous 2-propanol wasadded and the mixture kept at 80° C. under microwave irradiation for 50minutes. The mixture was then evaporated, distributed between 100 ml ofwater and 100 ml of EA, and the aqueous layer extracted twice using 20ml of EA each. The organic layer was then dried using MgSO₄ andevaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.4 gof the title compound, colorless oil. R_(f) (EA/HEP 1:4)=0.27

Step 2: 6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid methyl ester

1.3 g of 3-(3-bromo-phenyl)-oxetane, 1.3 g of2-methoxy-5-methoxycarbonylphenylboronic acid, 1.3 g of Na₂CO₃, 69 mg ofpalladium(II)acetate, and 160 mg of triphenylphosphine were combined and15 ml of DMF and 1 ml of water added. The mixture was stirred at 100° C.for 1 h and then allowed to cool to room temperature. 100 ml of EA werethen added and washed three times using 30 ml of water each. The organiclayer was then dried using MgSO₄ and evaporated. Chromatography onsilica gel using EA/HEP 1:3 yielded 1.3 g of the title compound,colorless oil.

Step 3: 6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid

The title compound was synthesized from6-methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid methyl ester inanalogy to example 443, step 5.

Step 4:1-[(6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylicacid methyl ester

The title compound was synthesized from6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid and1-amino-cycloheptanecarboxylic acid methyl ester in analogy to example126, step 4.

R_(f) (EA/HEP 1:1)=0.13

Step 5:1-[(6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylicacid

The title compound has been synthesized from1-[(6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylicacid methyl ester in analogy to example 442, step 5.

LC/MS (Method LC4): Rt=1.21 min. m/z=424.35 [MH⁺]

EXAMPLE 458Cis-4-Ethyl-1-[(6-methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylicacid

The title compound has been synthesized in analogy to example 457.

LC/MS (Method LC4): Rt=1.26 min. m/z=438.36 [MH⁺]

EXAMPLE 4591-[(6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-4-trifluoromethyl-cyclohexanecarboxylicacid

The title compound has been synthesized in analogy to example 457.

LC/MS (Method LC4): Rt=1.22 min. m/z=478.34 [MH⁺]

EXAMPLE 4601-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylicacid

Step 1: 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-benzeneboronic acid

50.0 g of [2-(3-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane wasdissolved using 500 ml of anhydrous THF and 64.6 ml of a 2.7M solutionof n-butyllithium in n-heptane added dropwise at −70° C. The reactionmixture was then stirred at −70° C. for 1 h. 40.2 ml oftriisopropylborate was then added dropwise at −70° C. and stirring wascontinued for 30 minutes at −70° C. The mixture was then allowed to warmto −20° C. and 500 ml of water added. The reaction mixture was thenallowed to warm to room temperature and extracted three times using 300ml of CH₂Cl₂ each. The organic layer was then dried using MgSO₄ andevaporated to yield 43.6 g of the title compound, used without furtherpurification.

Step 2: tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane

18.3 g of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-benzeneboronicacid, 510 mg of NiI₂, 19.9 g of sodium bis(trimethylsilyl)amide, and 250mg of trans-2-aminocyclohexanol hydrochloride were added to 14.0 ml of2-propanol and the mixture was stirred for 10 minutes at roomtemperature. Then, a solution of 10.0 g of 3-Iodo-oxetane in 6.0 ml of2-propanol was added and the reaction mixture kept at 80° C. undermicrowave irradiation for 30 minutes. The reaction mixture was thenpoured into 100 ml of a saturated aqueous NaHCO₃-solution and extractedthree times using 100 ml of EA each. The organic layer was then driedusing MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP(gradient) yielded 22.0 g of the title compound, colorless oil.

Step 3: 2-(3-Oxetan-3-yl-phenyl)-ethanol

9.0 g of tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silanewere dissolved using 200 ml of anhydrous THF and 92 ml of a 1M solutionof tetra-n-butylammonium fluoride in THF added at room temperature. Thereaction mixture was stirred at room temperature for 3 h and then pouredinto 500 ml of a saturated aqueous NaHCO₃-solution and extracted threetimes using 300 ml of EA each. The organic layer was then dried usingMgSO₄ and evaporated. Chromatography on silica gel using EA/HEP(gradient) yielded 4.9 g of the title compound, colorless oil.

Step 4: Toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester

4.9 g of 2-(3-Oxetan-3-yl-phenyl)-ethanol were dissolved using 30 ml ofCH₂Cl₂ and 9.5 ml of pyridine added. Then, 6.3 g of p-toluenesulfonylchloride was added at 0° C. and the reaction mixture stirred for 6 h atroom temperature. The reaction mixture was then evaporated, re-dissolvedusing 100 ml of EA and washed using 100 ml of a saturated aqueousNaHCO₃-solution. The aqueous layer was then extracted twice using 100 mlof EA each. The combined organic layer was then dried using MgSO₄ andevaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 2.0 gof the title compound, colorless oil.

Step 5: 3-Acetoxy-4-methoxy-benzoic acid

17.0 g of 3-Hydroxy-4-methoxy-benzoic acid were added to 51.6 g ofacetic ahydride and the mixture stirred at 140° C. for 3 h. The mixturewas then allowed to cool to 100° C., 50 ml of water added dropwise andthe temperature kept at 100° C. Then, 200 ml of water were added and themixture was stirred at 100° C. for 30 minutes. The mixture was thencooled and stirred at 0° C. for 1 h. The product was then isolated byfiltration, washed with 50 ml of water and dried under reduced pressureto yield 18.8 g of the title compound that was used without furtherpurification.

Step 6:1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester

80.3 mg of 3-Acetoxy-4-methoxy-benzoic acid were combined with 1 ml ofCH₂Cl₂, 3 μl of DMF added and 0.57 ml of a 2M solution of oxalylchloride in CH₂Cl₂ added dropwise under stirring at room temperature.Stirring was continued until the evolution of gas ceased. Then, thereaction mixture was evaporated, 5 ml of CH₂Cl₂ added and againevaporated. The residue (crude acid chloride) was then dissolved using 2ml of CH₂Cl₂ and added dropwise to an intensely stirred mixture of 100mg of 1-Amino-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester,5 ml of EA, and 10 ml of a saturated aqueous NaHCO₃-solution at 0° C.Stirring was continued for 1 h at room temperature. Then, the organiclayer was separated and the aqueous layer was extracted twice using 15ml of EA each. The organic layer was then dried using MgSO₄ andevaporated to yield 105 mg of the title compound that was used withoutfurther purification.

Step 7:1-(3-Hydroxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester

105 mg of1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester and 7.0 mg of K₂CO₃ were stirred in 4 ml of anhydrousmethanol for 1 h at room temperature. Then, 10.4 mg of K₂CO₃ were addedand stirring was continued for 2 h at room temperature. 10 ml of EA and10 ml of a 1N aqueous HCl-solution were then added. The layers wereseparated and the aqueous layer was extracted twice using 10 ml of EAeach. The combined organic layers were washed twice using 10 ml of asaturated aqueous NaHCO₃-solution, once using 10 ml of a 1N aqueousHCl-solution, and once using a 10 ml of a saturated aqueousNaCl-solution. The organic layer was then dried using MgSO₄ andevaporated to yield 60 mg of the title compound that was used withoutfurther purification.

Step 8:1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester

60 mg of1-(3-Hydroxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester, 53 mg of toluene-4-sulfonic acid2-(3-oxetan-3-yl-phenyl)-ethyl ester, and 66 mg of K₂CO₃ were added to 3ml of DMF and the mixture was stirred for 8 h at 40° C. Then, 27 mg oftoluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester were addedand stirring was continued for 8 h at 40° C. Then, 10 ml of EA and 15 mlof a half-saturated aqueous NaCl-solution were added. The layers wereseparated and the aqueous layer was extracted twice using 10 ml of EAeach. The combined organic layer was then dried using MgSO₄ andevaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 77 mgof the title compound, amorphous solid.

Step 9:1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylicacid

77 mg of1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl-cyclohexanecarboxylicacid methyl ester were dissolved using 3.5 ml of methanol and 173 μl ofa 1M aqueous solution of NaOH added. The mixture was stirred at 60° C.for 8 h. The mixture was then poured into 10 ml of water and acidifiedto pH=5 using 5% aqueous NaHSO₄-solution. The mixture was then extractedthree times using 15 ml of EA each. The organic layer was then driedusing MgSO₄ and evaporated.

LC/MS (Method LC4): Rt=1.23 min. m/z=522.29 [MH⁺]

EXAMPLE 461Cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

Step 1: 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid methyl ester

6.5 g of 3-chloro-4-methoxyphenylboronic acid, 5.0 g of methyl5-bromonicotinate, 1.3 g of tetrakis(triphenylphosphine)palladium(0),and 22.6 g of Cs₂CO₃ were stirred in 325 ml of DMF and 65 ml of waterfor 3 h at 45° C. The reaction mixture was then poured into 750 ml ofwater and extracted three times using 300 ml of EA each. The combinedorganic layers were then washed twice using 150 ml of water each. Theorganic layer was then dried using MgSO₄ and evaporated. Chromatographyon silica gel using EA/HEP (gradient) yielded 2.4 g of the titlecompound, colorless oil.

Step 2: 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid

5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid methyl ester was saponifiedin analogy to example 460, step 9.

Step 3:1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized from5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid and1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy toexample 126, step 4.

Step 4:Cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound has been synthesized in analogy to example 460, step9.

LC/MS (Method LC4): Rt=1.17 min. m/z=417.09 [MH⁺]

EXAMPLE 462Cis-4-Ethyl-1-[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

Step 1: 3-Hydroxy-4-iodo-benzoic acid methyl ester

37.0 g of methyl 4-amino-3-hydroxybenzoate were stirred in 200 ml ofwater and 200 g of ice and 300 ml of a saturated aqueous HCl-solutionadded. Stirring was continued for 5 minutes. A solution of 16.8 g NaNO₂was then added drop-wise at 0° C. and the mixture was stirred at 0° C.for 10 minutes. The resulting solution was then added portion-wise to asolution 73.5 g KI in 300 ml of water at 25° C. Stirring was continuedfor 1 h at 25° C.-30° C. The reaction mixture was the extracted threetimes using 200 ml of EA each. The organic layer was then washedsuccessively once using 100 ml of a 1M aqueous HCl-solution, once using100 ml of a saturated aqueous Na₂SO₃-solution, and three times using 100ml of a saturated aqueous NaHCO₃-solution each. The organic layer wasthen dried using MgSO₄ and evaporated. Chromatography on silica gelusing EAIHEP 1:2 yielded 37.0 g of the title compound, colorless oil.

R_(f) (EAIHEP 1:2)=0.34

Step 2: 4-Iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

10.0 g of 3-Hydroxy-4-iodo-benzoic acid methyl ester, 14.3 g of1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K₂CO₃ were stirred inanhydrous DMF at 80° C. for 10 h. Then, 14.3 g of1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K₂CO₃ were added andstirring was continued at 80° C. for 10 h. 400 ml of EA were then addedand the mixture was washed twice using 200 ml of water each. The organiclayer was then dried using MgSO₄ and evaporated. Chromatography onsilica gel using EAIHEP (gradient) yielded 11.5 g of the title compound,colorless oil.

Step 3: 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoicacid methyl ester

500 mg of 4-Iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester, 200 mgof methyl vinyl sulfone, 115 mg of tri-o-tolylphosphine, and 43 mg ofpalladium(II) acetate were stirred in 4 ml of acetonitrile and 1.5 ml ofdiisopropylethylamin for 2 h at 82° C. The reaction mixture was allowedto cool to room temperature. 10 ml of EA were then added and the mixturewas washed successively twice using 5 ml of water each and twice using 5ml of a saturated aqueous Na₂CO₃-solution. The organic layer was thendried using MgSO₄ and evaporated. Chromatography on silica gel usingEA/HEP 1:2 yielded 270 mg of the title compound. R_(f) (EA/HEP 1:2)=0.17

Step 4: 4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoic acidmethyl ester

250 mg of 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoicacid methyl ester were dissolved using 10 ml of methanol andhydrogenated under an 1.5 bar atmosphere of hydrogen using 50 mg of Pd/C(10%, 50% water) for 30 minutes. The catalyst was then removed byfiltration and the solution evaporated to yield 250 mg of the titlecompound that was used without further purification.

Step 5: 4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoic acid

The title compound was synthesized in analogy to example 443, step 5.

Step 6:cis-4-Ethyl-1-[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized from4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoic acid and1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy toexample 126, step 4.

Step 7:cis-4-Ethyl-1-[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 443, step 5.

LC/MS (Method LC4): Rt=1.32 min. m/z=516.39 [MH⁺]

EXAMPLE 463Cis-1-{[7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

Step 1:7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid methyl ester

1.9 g of7-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid methyl ester (example YY, step 4), 1.5 g of4-bromo-2-chloro-1-methoxybenzene, 152 mg of triphenylphosphine, 65 mgof palladium(II) acetate, and 2.4 g of K₂CO₃ were stirred in 30 ml ofDMF and 3 ml of water under an argon atmosphere at 100° C. for 4 h. 200ml of water were then added and the mixture was extracted three timesusing 100 ml of EA each. The organic layer was then dried using MgSO₄and evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded330 mg of the title compound, colorless oil. R_(f) (EA/HEP 1:5)=0.29

Step 2:7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid

The title compound was synthesized in analogy to example 442, step 5.

Step 3:cis-1-{[7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid methyl ester

The title compound was synthesized form7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylicacid and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester inanalogy to example 126, step 4.

Step 4:Cis-1-{[7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]-amino}-4-ethyl-cyclohexanecarboxylicacid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt=1.42 min. m/z=496.28 [MH⁺]

Pharmacological Tests

A) Determination of Edg-2 Receptor Inhibition by Fluorescence ImagingPlate Reader (FLIPR) Measurements

The inhibition of the Edg-2 receptor (LPA₁ receptor) by the compounds ofthe invention was quantified by the inhibitory effect on theLPA-mediated calcium liberation in a cell-based calcium fluorescenceassay by use of Chinese hamster ovarian (CHO) cells in which the humanEdg-2 receptor was stably overexpressed (Flp-In system, Invitrogen). Inorder to enforce G-Protein coupling and to direct signaling towards Ca²⁺liberation, the overexpressed receptor additionally had a C-terminalsequence of a modified G-protein (G_(αi4qi4)) (WO 02/04665). Changes inintracellular calcium were determined by fluorescence measurement withthe calcium-sensitive dye fluo-4 (Invitrogen) in a fluorescence imagingplate reader (FLIPR, Molecular Dynamics).

CHO cells stably overexpressing the human Edg-2 receptor were seeded(40.000 per well) in black clear-bottomed poly-D-lysine-coated 96 wellplates (Becton Dickinson, Biocoat cellware) approximately 18-24 h priorto the experiments. Cells were grown in an incubator at 37° C., 5%carbon dioxide and 95% humidity in cell culture media based on F-12glutamax media (Gibco, #31765) supplemented with 1% (vol/vol)penicilline/streptomycine (PAN, #P06-07100), 10% (vol/vol) fetal calfserum (FCS, PAA, #A15-151) and hygromycin B (Invitrogen, #10687-010) 300mg/l (final concentrations).

Prior to the FLIPR experiment, cells were loaded with fluo-4acetoxymethyl ester (fluo-4 AM, Invitrogen, #F14202) for 60 min in anincubator at 37° C., 5% carbon dioxide and 95% humidity in dye-loadingbuffer consisting of Hanks' Balanced Salt Solution (HBSS, Invitrogen,#14065049) supplemented with fluo-4 AM at 2 μM (all data given for finalconcentration), Pluronic® F-127 0.05% (vol/vol) (Invitrogen, #P-3000MP), HEPES 20 mM (Gibco, #15630), probenecid 2.5 mM (Sigma, #P-8761) andbovine serum albumin 0.05% (BSA, Sigma, #A-6003), adjusted to pH 7.5with sodium hydroxide. During cell loading, fluo-4 AM is cleaved byintracellular esterase resulting in trapping of the dye fluo-4 withinthe cells. Loading was terminated by washing of the cells in a cellwasher (Tecan Power washer) three times with the buffer specified aforebut without fluo-4 AM and BSA. This latter buffer was also used as thebuffer in the subsequent cell fluorescence measurements.

The dye-loaded and washed cells were pre-incubated for approximately 5min with various concentrations of the test compound added as a solutionin DMSO (0.3% vol/vol maximum final concentration of DMSO), or with DMSOin the respective concentration only (positive control). Subsequentaddition of LPA (18:1,1-oleoyl-sn-glycerol 3-phosphate; 100 nM finalconcentration) leads to liberation of intracellular calcium frominternal stores resulting in a large transient increase of the fluo-4fluorescence signal which was monitored over approximately 3 min. Thepercent inhibition caused by the test compound was determined from themaximum fluorescence response after LPA addition to cells pre-incubatedwith the compound as compared to the maximum fluorescence response afterLPA addition to cells pre-incubated with DMSO only. All fluorescencevalues were corrected for the baseline fluorescence values obtained withcells which were pre-incubated with DMSO only and were not treated withLPA (baseline control). All measurements were performed in triplicate.From the percent inhibitions the inhibitory concentration IC₅₀ wasdetermined.

Inhibitory concentrations IC₅ so of various example compounds are givenin table 23, wherein “a” denotes an IC₅₀ of less than 0.1 μM, “b”denotes an IC₅₀ between 0.1 μM and 1 μM, and “c” denotes an IC₅₀ between1 μM and 30 μM.

TABLE 23 Inhibitory concentrations IC₅₀ for inhibition of the Edg-2receptor Example IC₅₀ 1 b 2 a 3 a 4 b 5 a 6 b 7 a 8 a 9 a 10 a 11 b 12 b13 a 14 b 15 c 16 a 17 a 18 b 19 b 20 a 21 b 22 a 23 b 24 b 25 c 26 a 27a 28 a 29 a 30 a 31 a 32 c 33 a 34 c 35 c 36 b 37 c 38 b 39 c 40 b 41 a43 a 44 b 45 b 46 a 47 a 48 c 49 c 50 a 51 a 52 c 53 b 54 a 55 b 56 a 57a 58 c 59 a 60 b 61 b 62 a 63 a 64 b 65 a 66 b 66 b 67 b 67 c 68 a 69 b70 a 71 a 72 a 73 c 74 a 75 a 76 a 77 a 78 b 79 a 80 a 81 a 82 a 83 a 84c 85 a 86 c 87 c 88 a 89 c 90 a 91 a 92 c 93 c 94 b 95 b 96 a 97 a 98 a99 a 100 a 103 b 104 b 105 b 106 c 107 a 108 a 109 a 110 a 111 a 112 a113 b 114 b 115 c 116 c 117 c 118 c 119 a 121 b 122 a 123 a 124 b 125 a126 a 127 a 128 b 129 b 130 a 131 a 132 a 133 a 134 a 205 a 206 a 207 a208 a 299 a 300 a 301 a 302 a 303 a 304 a 305 a 306 a 307 a 308 a 309 a310 a 311 a 312 b 313 a 314 a 315 a 316 a 317 a 318 a 319 a 320 a 326 a327 a 328 b 329 a 330 c 331 a 332 a 333 a 334 b 351 a 352 a 355 a 356 a357 a 358 a 359 a 360 a 361 a 362 a 363 b 364 a 365 b 366 b 367 b 368 b369 b 370 a 371 b 372 b 373 b 374 a 375 a 376 a 377 a 378 a 379 a 380 a381 a 382 a 383 a 384 a 385 a 386 a 387 a 388 a 389 a 390 a 391 a 392 a393 a 394 a 395 a 396 a 397 a 398 a 399 a 400 a 401 a 402 a 403 a 404 a405 a 406 b 407 a 408 b 409 a 410 a 411 a 412 a 413 a 414 a 415 a 416 a417 a 418 a 419 a 420 b 421 b 422 b 423 a 424 a 425 b 426 b 427 b 428 a429 b 430 b 431 b 432 b 433 a 434 b 435 b 436 b 437 a 438 a 439 b 440 b441 c 442 a 443 b 444 b 445 a 446 a 447 a 448 a 449 b 450 a 451 a 452 b453 a 454 a 455 a 456 a 457 b 458 a 459 a 460 b 461 a 462 b 463 aB) In vivo Antihypertrophic and Renoprotective Activity

The in vivo pharmacological activity of the compounds of the inventioncan be investigated, for example, in the model of DOCA-salt sensitiverats with unilateral nephrectomy. Briefly, in this model unilateralnephrectomy of the left kidney (UNX) is performed on Sprague Dawley ratsof 150 g to 200 g of body weight. After the operation as well as at thebeginning of each of the following weeks 30 mg/kg of body weight of DOCA(desoxycorticosterone acetate) are administered to the rats bysubcutaneous injection. The nephrectomized rats treated with DOCA aresupplied with drinking water containing 1% of sodium chloride (UNX/DOCArats). The UNX/DOCA rats develop high blood pressure, endothelialdysfunction, myocardial hypertrophy and fibrosis as well as renaldysfunction. In the test group (UNX/DOCA Test) and the placebo group(UNX/DOCA Placebo), which consist of randomized UNX/DOCA rats, the ratsare treated orally by gavage in two part administrations at 6 a.m. and 6p.m. with the daily dose of the test compound (for example 10 mg/kg ofbody weight dissolved in vehicle) or with vehicle only, respectively. Ina control group (control), which consists of animals which have not beensubjected to UNX and DOCA administration, the animals receive normaldrinking water and are treated with vehicle only. After five weeks oftreatment, systolic blood pressure (SBP) and heart rate (HR) aremeasured non-invasively via the tail cuff method. For determination ofalbuminuria and creatinine, 24 h urine is collected on metabolic cages.Endothelial function is assessed in excised rings of the thoracic aortaas described previously (W. Linz et al., JRAAS (Journal of therenin-angiotensin-aldosterone system) 7 (2006), 155-161). As a measureof myocardial hypertrophy and fibrosis, heart weight, left ventricularweight and the relation of hydroxyproline and proline are determined inexcised hearts.

We claim:
 1. A compound of formula I,

wherein ring A is a 5- or 6-membered carbocyclic ring, which issaturated or comprises 1 double bond, wherein ring A is optionallysubstituted by one or more identical or different substituents chosenfrom the series consisting of halogen, R¹, R², (C₂-C₆)-alkenyl, HO—,R¹—O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—, R¹—S(O)₂—O—, R¹—S(O)_(m)—,H₂N—, R¹—NH—, R¹—N(R¹)—, R¹—C(O)—NH—, R¹—C(O)—N(R¹)—, R¹—S(O)₂—NH—,R¹—S(O)₂—N(R¹)—, R¹—C(O)—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—,R¹—N(R¹)—C(O)—, H₂N—S(O)₂—, R¹—NH—S(O)₂—, R¹—N(R¹)—S(O)₂—, F₅S—, NC—,oxo and methylene; Y is chosen from the series consisting of N(R¹⁰), O,N═C(R¹⁴) and C(R¹⁵)═N; Z is chosen from the series consisting of N andC(R¹⁶); R⁰ is chosen from the series consisting of hydrogen and R¹; R¹is chosen from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-; R² is(C₁-C₄)-alkyl which is substituted by one or more identical or differentsubstituents chosen from the series consisting of HO— and(C₁-C₄)-alkyl-O—; R¹⁰ is chosen from the series consisting of hydrogenand R¹¹; R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ and R⁵⁸ are,independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ andR⁵⁸, chosen from the series consisting of (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- which are all optionally substitutedby one or more identical or different substituents R⁷⁰; R¹², R¹³, R¹⁴,R¹⁵ and R¹⁶ are independently of each other chosen from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, H₂N—, (C₁-C₄)-alkyl-NH—,(C₁-C₄)-alkyl-N((C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-C(O)—and NC—, or R¹³ orR¹⁴, together with the one of the groups R²¹ and R²² which is not thegroup of the formula II, forms a chain consisting of 3 to 5 chainmembers of which 0, 1 or 2 chain members are identical or differenthetero chain members chosen from the series consisting of N(R¹⁷), O andS, but two hetero chain members cannot be present in adjacent positions,and the other chain members are identical or different groupsC(R¹⁸)(R¹⁸); R¹⁷ and R²⁵ are independently of each other chosen from theseries consisting of hydrogen and (C₁-C₄)-alkyl; R¹⁸, independently ofeach other group R¹⁸, is chosen from the series consisting of hydrogen,fluorine and (C₁-C₄)-alkyl, or two of the groups R¹⁸ bonded to the samecarbon atom, together with the carbon atom carrying them, form a3-membered to 6-membered cycloalkane ring which is optionallysubstituted by one more identical or different substituents chosen fromthe series consisting of fluorine and (C₁-C₄)-alkyl; R²⁰ is chosen fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; one of the groupsR²¹ and R²² is a group of the formula IIR²⁴—R²³—  II and the other of the groups R²¹ and R²² is chosen from theseries consisting of hydrogen, halogen, R³⁰, HO—, R³⁰—O—, R³⁰—C(O)—O—,R³⁰—S(O)₂—O—, R³⁰—S(O)_(m)—, H₂N—, R³⁰—NH—, R³⁰—N(R³⁰)—, R³⁰—C(O)—NH—,R³⁰—C(O)—N(R⁷¹)—, R³⁰—S(O)₂—NH—, R³⁰—S(O)₂—N(R⁷¹)—, R³⁰—C(O)—, HO—C(O)—,R³⁰—O—C(O)—, H₂N—C(O)—, R³⁰—NH—C(O)—, R³⁰—N(R³⁰)—C(O)—, H₂N—S(O)₂—,R³⁰—NH—S(O)₂—, R³⁰—N(R³⁰)—S(O)₂—, NC—, O₂N— and Het¹, or together withR¹³ or R¹⁴ forms a chain as specified in the definition of R¹³ and R¹⁴;R²³ is a direct bond or a chain consisting of 1 to 5 chain members ofwhich 0, 1 or 2 chain members are identical or different hetero chainmembers chosen from the series consisting of N(R²⁵), O, S, S(O) andS(O)₂, but two hetero chain members can be present in adjacent positionsonly if one of them is chosen from the series consisting of S(O) andS(O)₂ and the other is chosen from the series consisting of N(R²⁵), Oand S, and the other chain members are identical or different groupsC(R²⁶)(R²⁶); R²⁴ is a 3-membered to 10-membered, monocyclic or bicyclicring, which is saturated and contains 0 or 1 hetero ring members, or isunsaturated and contains 0, 1 or 2 identical or different hetero ringmembers, wherein the hetero ring members are chosen from the seriesconsisting of N, N(R³²), O, S, S(O) and S(O)₂, and wherein the ring isoptionally substituted on ring carbon atoms by one or more identical ordifferent substituents chosen from the series consisting of halogen,R³³, oxetanyl, HO—, R³³—O—, R³³—C(O)—O—, R³³—S(O)₂—O—, R³³—S(O)_(m)—,H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—,R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, R³³—C(O)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, H₂N—S(O)₂—, R³³—NH—S(O)₂—,R³³—N(R³³)—S(O)₂—, NC—, O₂N— and oxo ; R²⁶, independently of each othergroup R²⁶, is chosen from the series consisting of hydrogen, fluorine,(C₁-C₄)-alkyl and HO—, or two groups R²⁶ bonded to the same carbon atomtogether are oxo, or two of the groups R²⁶ or one group R²⁵ and onegroup R²⁶, together with the comprised chain members, form a 3-memberedto 7-membered monocyclic ring which is saturated and contains 0, 1 or 2identical or different hetero ring members chosen from the seriesconsisting of N, N(R³⁴), O, S, S(O) and S(O)₂, which ring is optionallysubstituted on ring carbon atoms by one more identical or differentsubstituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl; R³² and R³⁴ are independently of each other chosen fromthe series consisting of hydrogen, R³⁵, R³⁵—S(O)₂—, R³⁵—C(O)—,R³⁵—O—C(O)— and phenyl; R⁵⁰ is chosen from the series consisting ofR⁵¹—O— and R⁵²—N(R⁵³)—; R⁵¹ is chosen from the series consisting ofhydrogen and R⁵⁴; R⁵² is chosen from the series consisting of hydrogen,R⁵⁵, NC— and R⁵⁶—S(O)₂—; R⁵³ is chosen from the series consisting ofhydrogen and R⁵⁷; R⁵⁶ is chosen from the series consisting of R⁵⁸ andphenyl; R⁶⁰, independently of each other group R⁶⁰, is chosen from theseries consisting of hydrogen and (C₁-C₄)-alkyl; R⁷⁰ is chosen from theseries consisting of HO—, R⁷¹—O—, R⁷¹—C(O)—O—, R⁷¹—S(O)_(m)—, H₂N—,R⁷¹—NH—, R⁷¹—N(R⁷¹)—, R⁷¹—C(O)—NH—, R⁷¹—C(O)—N(R⁷¹)—, R⁷¹—S(O)₂—NH—,R⁷¹—S(O)₂—N(R⁷¹)—, HO—C(O)—, R⁷¹—O—C(O)—, H₂N—C(O)—, R⁷¹—NH—C(O)—,R⁷¹—N(R⁷¹)—C(O)—, H₂N—S(O)₂—, R⁷¹—NH—S(O)₂—, R⁷¹—N(R⁷¹)—S(O)₂—and oxo;R⁷¹, independently of each other group R⁷¹, is chosen from(C₁-C₄)-alkyl, (C₃-C₄)-cycloalkyl and (C₃-C₄)-cycloalkyl-(C₁-C₂)-alkyl-;Het¹ is a monocyclic 4-membered to 7-membered heterocyclic ring whichcomprises 1 or 2 identical or different hetero ring members chosen fromthe series consisting of N, N(R⁶⁰), O, S, S(O) and S(O)₂, which ring issaturated and is optionally substituted by one or more identical ordifferent substituents chosen from the series consisting of fluorine and(C₁-C₄)-alkyl; m, independently of each other number m, is an integerchosen from the series consisting of 0, 1 and 2; phenyl, independentlyof each other group phenyl, is optionally substituted by one or moreidentical or different substituents chosen from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and NC—, unless specifiedotherwise; cycloalkyl, independently of each other group cycloalkyl, andindependently of any other substituents on cycloalkyl, is optionallysubstituted by one or more identical or different substituents chosenfrom fluorine and (C₁-C₄)-alkyl; and alkyl, alkenyl and alkynyl,independently of each other group alkyl, alkenyl and alkynyl, andindependently of any other substituents on alkyl, alkenyl and alkynyl,is optionally substituted by one or more fluorine substituents; providedthat the compound of the formula I is not1-[(biphenyl-4-carbonyl)-amino]-cyclohexanecarboxylic acid,1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid, 1-[4-(2-piperidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylicacid, 1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylicacid,1-{[4-(2-oxo-pyrrolidin-1-yl)-furan-2-carbonyl]-amino}-cyclohexanecarboxylicacid,1[4,6-dimethyl-pyrimidin-2-ylsulfanyl)-benzoylamino]-cyclopentanecarboxylicacid ethyl ester,1-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-cyclopropanecarboxylic acidmethyl ester or1-[2-chloro-4-(3-hydroxy-benzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylicacid; or a stereoisomeric form thereof or a mixture of stereoisomericforms in any ratio, or a physiologically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein ring A is a cyclohexane ring,which is optionally substituted by one or more identical or differentsubstituents chosen from the series consisting of halogen, R¹, R²,(C₂-C₆)-alkenyl, HO—, R¹ 1O—, phenyl-(C₁-C₄)-alkyl-O—, R¹—C(O)—O—,R¹—S(O)₂—O—, HO—C(O)—, R¹—O—C(O)—, H₂N—C(O)—, R¹—NH—C(O)—,R¹—N(R¹)—C(O)— and oxo; or a stereoisomeric form thereof or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof.
 3. The compound according to claim 1, wherein Y is C(R¹⁵)═N;and Z is C(R¹⁶); or a stereoisomeric form thereof or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof.
 4. The compound according to claim 1, wherein R²¹ is chosenfrom the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,HO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, (C₁-C₄)-alkyl-C(O)—, NC— and Het¹, or togetherwith R¹³ or R¹⁴ forms a chain as specified in the definition of R¹³ andR¹⁴; and R²² is a group of the formula IIR²⁴—R²³—  II R²³ is a direct bond or a chain consisting of 2, 3 or 4chain members of which 0 or 1 chain members are hetero chain memberschosen from the series consisting of N(R²⁵), O, S, S(O) and S(O)₂, andthe other chain members are identical or different groups C(R²⁶)(R²⁶);or a stereoisomeric form thereof or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof.
 5. The compoundaccording to claim 1, wherein R²⁴ is a 3-membered to 7-memberedmonocyclic ring or a 7-membered to 10-membered bicyclic ring, whichrings are saturated and contain 0 or 1 hetero ring members, or areunsaturated and contain 0, 1 or 2 identical or different hetero ringmembers chosen from the series consisting of N, N(R³²), O, S, S(O) andS(O)₂, and which rings are optionally substituted on ring carbon atomsby one or more identical or different substituents chosen from theseries consisting of halogen, R³³, oxetanyl, HO—, R³³—O—, R³³—S(O)_(m)—,H₂N—, R³³—NH—, R³³—N(R³³)—, R³³—C(O)—NH—, R³³—C(O)—N(R⁷¹)—,R³³—S(O)₂—NH—, R³³—S(O)₂—N(R⁷¹)—, H₂N—S(O)₂—NH—, R³³—NH—S(O)₂—NH—,R³³—N(R³³)—S(O)₂—NH—, H₂N—S(O)₂—N(R⁷¹)—, R³³—NH—S(O)₂—N(R⁷¹)—,R³³—N(R³³)—S(O)₂—N(R⁷¹)—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)—, NC— and oxo; and R³² is chosen from theseries consisting of hydrogen, R³⁵, R³⁵—C(O)—, R³⁵—O—C(O)— and phenyl;or a stereoisomeric form thereof or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof.
 6. The compoundaccording to claim 1, wherein ring A is a cyclohexane ring which isoptionally substituted by one or two identical or different substituentschosen from the series consisting of halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—; Y is C(R¹⁵)═N; Z is C(R¹⁶); R¹², R¹³, R¹⁵ and R¹⁶ areindependently of each other chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl; or R¹³ forms together with R²¹ a chainwhich is chosen from the series consisting of —O—C(R¹⁸)(R¹⁸)—O—,—CH₂—CH₂—CH₂, —CH₂—O—CH₂—, —CH₂—CH₂—CH₂—CH₂— and—O—C(R¹⁸)(R¹⁸)—C(R¹⁸)(R¹⁸)—O; R¹⁸ is chosen from the series consistingof hydrogen or fluorine; R²¹ is chosen from the series consisting ofhydrogen, halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-C(O)—, (C₁-C₄)-alkyl-O—(C₁-C₄)alkyl-, HO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, NC— and oxetanyl, or together with R¹³forms a chain as specified in the definition of R¹³; R²² is a group ofthe formula IIR²⁴—R²³—  II R²³ is a direct bond or a chain consisting of 2, 3 or 4chain members of which 0 or 1 chain members are hetero chain memberschosen from the series consisting of O and S, and the other chainmembers are identical or different groups C(R²⁶)(R²⁶); R²⁴ is a benzenering which is optionally substituted by one or more identical ordifferent substituents chosen from the series consisting of halogen,R³³, oxetanyl, HO—, R³³—O—, R³³—S(O)_(m)—, H₂N—, R³³—NH—, R³³—N(R³³)—,R³³—C(O)—NH—, R³³—S(O)₂—NH—, HO—C(O)—, R³³—O—C(O)—, H₂N—C(O)—,R³³—NH—C(O)—, R³³—N(R³³)—C(O)— and NC—; R²⁶, independently of each othergroup R²⁶, is chosen from the series consisting of hydrogen, fluorine,(C₁-C₄)-alkyl, or two of the groups R²⁶ which are bonded to the samecarbon atom in the chain, together with the carbon atom carrying them,form a cyclopropane ring or an oxetane ring; R³³, independently of eachother group R³³, is chosen from the series consisting of (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, which are alloptionally substituted by one or more identical or differentsubstituents R⁷⁰; R⁵⁰ is chosen from the series consisting of R⁵¹O— andR⁵²(R⁵³)N—; R⁵¹, R⁵² and R⁵³ are independently of each other chosen fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; R⁷⁰ is chosen fromthe series consisting of HO— and R⁷¹—O—; R⁷¹ is (C₁-C₄)-alkyl; m,independently of each other number m, is an integer chosen from theseries consisting of 0 and 2; cycloalkyl, independently of each othergroup cycloalkyl, and independently of any other substituents oncycloalkyl, is optionally substituted by one or more identical ordifferent substituents chosen from fluorine and (C₁-C₄)-alkyl; andalkyl, independently of each other group alkyl, and independently of anyother substituents on alkyl, is optionally substituted by one or morefluorine substituents; or a stereoisomeric form thereof or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof.
 7. A compound according to claim 1, which is:trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid,cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid,trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylicacid,cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid,cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid,trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid,trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid,cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid,trans-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid,trans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid,cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid,cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid,cis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid,trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid, orcis-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid, or a stereoisomeric form thereof or a mixture of stereoisomericforms in any ratio, or a physiologically acceptable salt thereof.
 8. Aprocess for preparing the compound according to claim 1, comprisingreacting a compound of formula III with a compound of formula IV,

wherein the ring A and the groups Y, Z, R²⁰ to R²² and R⁵⁰ in thecompounds of the formulae III and IV are defined as in claim 1 andadditionally functional groups can be present in protected form or inthe form of a precursor group, and the group G in the compound offormula IV is HO—, (C₁-C₄)-alkyl-O— or halogen.
 9. A pharmaceuticalcomposition comprising the compound according to claim 1 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 10. The compound according to claim 1, which iscis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 11. The compoundaccording to claim 1, which iscis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 12. The compoundaccording to claim 1, which istrans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 13. The compoundaccording to claim 1, which istrans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 14. The compoundaccording to claim 1, which iscis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 15. The compoundaccording to claim 1, which istrans-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methyl-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 16. The compoundaccording to claim 1, which istrans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 17. The compoundaccording to claim 1, which iscis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methyl-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 18. The compoundaccording to claim 1, which iscis-1-({5[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 19. The compoundaccording to claim 1, which iscis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 20. The compoundaccording to claim 1, which istrans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethyl-cyclohexanecarboxylicacid, or a physiologically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising the compound according to claim 10 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition comprising thecompound according to claim 11 or a physiologically acceptable saltthereof and a pharmaceutically acceptable carrier.
 23. A pharmaceuticalcomposition comprising the compound according to claim 12 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 24. A pharmaceutical composition comprising thecompound according to claim 13 or a physiologically acceptable saltthereof and a pharmaceutically acceptable carrier.
 25. A pharmaceuticalcomposition comprising the compound according to claim 14 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 26. A pharmaceutical composition comprising thecompound according to claim 15 or a physiologically acceptable saltthereof and a pharmaceutically acceptable carrier.
 27. A pharmaceuticalcomposition comprising the compound according to claim 16 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 28. A pharmaceutical composition comprising thecompound according to claim 17 or a physiologically acceptable saltthereof and a pharmaceutically acceptable carrier.
 29. A pharmaceuticalcomposition comprising the compound according to claim 18 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 30. A pharmaceutical composition comprising thecompound according to claim 19 or a physiologically acceptable saltthereof and a pharmaceutically acceptable carrier.
 31. A pharmaceuticalcomposition comprising the compound according to claim 20 or aphysiologically acceptable salt thereof and a pharmaceuticallyacceptable carrier.